Synthesis and intermediates

ABSTRACT

The invention relates to novel synthesis methods for the preparation of statin derivatives, which methods proceed by way of a key intermediate of formula I 
     
       
         
         
             
             
         
       
     
     wherein X is halogen, acyloxy, activated hydrocarbyloxy, activated hydrocarbylthio or —N(CH 3 )OCH 3 , R a  is a hydroxy-protecting group and R b  is a carboxy-protecting group, and, as well as to the compound of formula I, to further new intermediates and methods for their preparation by Friedel-Crafts acylation.

This application is a divisional of application Ser. No. 10/482,463,filed on Dec. 31, 2003, pending, which is a 371 of international app.No. PCT/EP2002/07307, filed Jul. 2, 2002, which claims priority to EP018106708, filed Jul. 6, 2001. all of which are herein incorporated byreference.

SUMMARY OF THE INVENTION

The invention relates to novel preparation processes for the preparationof 3,5-dihydroxyheptanoic acid derivatives and to novel intermediatesand processes for their preparation. The dihydroxyheptanoic acidderivatives and the intermediates are suitable for advantageoussyntheses of statins.

BACKGROUND TO THE INVENTION

Statins are a class of pharmaceuticals that inhibit the enzymehydroxymethylglutaryl CoA reductase (HMG-CoA-R) and are therefore widelyused as hypolipidaemic agents and agents that lower the level ofcholesterol in the blood (hypocholesterollipidaemic agents). Allsynthetically prepared HMG-CoA-R inhibitors have, as common structuralfeatures, an aromatic base structure and the so-called statin sidechain, as symbolised by the following formula:

(wherein Aryl denotes aromatic, heterocyclic or aromatic-heterocyclic,unsubstituted or substituted, mono-, di- or poly-cyclic ring systems).Such a structural unit can be found in a whole range of pharmaceuticallyactive agents, such as cerivastatin (Bayer AG), fluvastatin (Novartis),itavastatin (NK-104; Kowa Company Ltd.), BMY 22089 (Bristol-MyersSquibb), rosuvastatin (S-4522, AstraZeneca/Shionogi), glenvastin(Hoechst(Aventis) and atorvastatin (Warner-Lambert/Gödecke-ParkeDavies/Pfizer).

The aim of the present invention is to provide new efficient methods ofsynthesising some known statin derivatives and to provide newintermediate compounds.

GENERAL DESCRIPTION OF THE INVENTION

Key steps in the synthesis according to the invention are earlyintroduction of the correct absolute stereochemistry at C-3 (R) andsubsequent regioselective chain lengthening. Unlike the linear synthesisprocesses in the prior art, the use of the novel statin side chainbuilding blocks allows a convergent synthesis. The invention relatesalso to novel intermediates.

DETAILED DESCRIPTION OF THE INVENTION

The process according to the invention is based on the key intermediateof formula I

wherein X is halogen, acyloxy, activated hydrocarbyloxy, activatedhydrocarbylthio or —N(CH₃)—OCH₃, R_(a) is a hydroxy-protecting group andR_(b) is a carboxy-protecting group, which intermediate is eitherethenylated, as described below:

Starting from the reaction of the key intermediate of formula (I) withan ethylene of formula III

wherein Y_(a) is halogen or hydrogen, there is obtained a keto compoundof formula III

wherein Y_(a) is halogen or hydrogen, X_(a) is halogen (preferred) oracyloxy, R_(a) is hydrogen (obtainable after selective removal of ahydroxy-protecting group R_(a)) or a hydroxy-protecting group and R_(b)is a carboxy-protecting group; the compound of formula III is reactedfurther in one of the following three ways:(1) A compound of formula III wherein Y_(a) is hydrogen and X_(a) ishalogen (preferred) or acyloxy, while R_(a) and R_(b) are as defined forcompounds of formula III, is reacted with a salt of hydrazoic acid toform an azido compound of formula IV

wherein R_(a) is hydrogen or a hydroxy-protecting group and R_(b) is acarboxy-protecting group. The compound of formula IV (when R_(a) is ahydroxy-protecting group, after prior selective removal thereof) is thenreduced diastereoselectively by means of a suitable reagent to form asyn-diol compound of formula V

wherein R_(a)′ is hydrogen and R_(c)′ is hydrogen; or, after subsequentintroduction of protecting groups, R_(a)′ and R_(c)′ are eachindependently of the other hydrogen or a protecting group, with theproviso that at least one of the two radicals is a protecting group, orR_(a)′ and R_(c)′ together are a bridging hydroxy-protecting group; andR_(b) is a carboxy-protecting group;and, in a case where the introduction of a bridging hydroxy-protectinggroup is desirable, when R_(a)′ and R_(c)′ are each hydrogen, thebridging hydroxy-protecting group formed by R_(a)′ and R_(c)′ togetherbeing introduced using a suitable reagent;and the compound of formula V so obtainable is then reduced to thecorresponding amino compound of formula VI

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogenor a hydroxy-protecting group or together are a bridginghydroxy-protecting group, and R_(b) is a carboxy-protecting group.

That compound can then be used further directly for the preparation of astatin derivative the aryl radical of which is bonded to the side chainvia nitrogen, for example for the preparation of atorvastatinanalogously to the conditions described in WO 89/07598.

(2) Alternatively, a compound of formula III can be reacted as follows:a compound of formula III wherein Y_(a) is hydrogen or halogen, iodineor especially chlorine or bromine and X_(a) is halogen (preferred) oracyloxy, while R_(a) and R_(b) are as defined for compounds of formulaIII, is converted in the presence of a base, with elimination ofhydrohalic acid HX, into an olefin of formula VII

wherein Y_(a)′ is hydrogen or halogen, especially iodine or moreespecially chlorine or bromine, R_(a) is hydrogen or ahydroxy-protecting group and R_(b) is a carboxy-protecting group. Such acompound is used further as described below under Variant (B), or thecorresponding compound wherein Y_(a)′ is iodine can be obtained byreaction with an iodide salt.

The compound of formula VII, or the corresponding compound whereinY_(a)′ is iodine, can then be converted into the correspondingHMG-CoA-reductase inhibitor, for example by Heck coupling with aryliodides, aryl triflates or aryl bromides that introduce thecomplementary aryl radical for the formula described under “Backgroundto the invention”, or, after reduction of the double bond, can be usedfurther.

Another further use of such a compound is brought about by reactionthereof with an iodide salt, the corresponding compound of formula VIIwherein Y_(a)′ is iodine being obtained. The compound of formula VII, orthe corresponding compound wherein Y_(a)′ is iodine, can then beconverted into the corresponding HMG-CoA-reductase inhibitor, forexample by Heck coupling with aryl iodides, aryl triflates or arylbromides that introduce the complementary aryl radical for the formuladescribed under “Background to the invention”, or, after reduction ofthe double bond, can be used further.

For the preparation of other statins, preferably a compound of formulaVII as obtained above wherein the radicals are as defined for formulaVII, preferably wherein Y_(a)′=hydrogen, is then, if necessary, freed ofa hydroxy-protecting group R_(a) and subsequently reduceddiastereoselectively by means of a suitable reagent to form a syn-diolcompound of formula VIII

wherein R_(a)′ is hydrogen and R_(c)′ is hydrogen, or, after subsequentintroduction of protecting groups, R_(a)′ and R_(c)′ are eachindependently of the other hydrogen or a protecting group, with theproviso that at least one of the two radicals is a protecting group, orR_(a)′ and R_(c)′ together are a bridging hydroxy-protecting group;R_(b) is a carboxy-protecting group, and Y_(a)′ is hydrogen or halogen(especially iodine or more especially chlorine or bromine);and, in a case where the introduction of a bridging hydroxy-protectinggroup is desirable, if necessary, when R_(a)′ and R_(c)′ are eachhydrogen, the bridging hydroxy-protecting group formed by R_(a)′ andR_(c)′ together being introduced using a suitable reagent.

The resulting compound of formula VIII is then preferably cleavedoxidatively to form an aldehyde of formula IX

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogenor, preferably, a hydroxy-protecting group or together are a bridginghydroxy-protecting group; and R_(b)′ is a carboxy-protecting group; thecompound of formula X can be used directly as synthon for thepreparation of statin derivatives, especially of itavastatin (see Bull.Chem. Soc. Jpn. 68, 364 (1995)), BMY 22089 (see J. Med. Chem. 32, 2038(1989)) or glenvastin (see Tetrahedron Lett. 31, 2545 (1990)), or it isreacted further with iodoform, diiodomethane or methyl iodide to form aniodine compound of formula X

wherein R_(a)′, R_(b)′ and R_(c)′ are as defined for compounds offormula IX; if desired, one or more or all of the protecting groups canbe removed therefrom. That compound can then be reacted under Suzukicoupling conditions, which may be modified if necessary, to formHMG-CoA-reductase inhibitors.(3) As a third alternative (advantageous over reaction method (1),because the azide group is introduced only later and so the specialprecautionary measures to be taken when using azides are required onlylater), a compound of formula III wherein X_(a) is halogen, especiallyiodine or more especially chlorine or bromine, or acyloxy, and Y_(a) ishydrogen, (when R_(a) is a hydroxy-protecting group, after removalthereof) R_(a) is hydrogen and R_(b) is a carboxy-protecting group canbe converted diastereoselectively by means of a suitable reagent into asyn-diol compound of formula Va

wherein X_(a) is halogen, especially iodine or more especially chlorineor bromine, or acyloxy, and R_(a)′ and R_(c)′ are as defined forcompounds of formula V and R_(b) is as defined for compounds of formulaIII; and the compound of formula Va is then reacted with a salt ofhydrazoic acid to form a compound of formula V described above whereinR_(a)′ and R_(c)′ are each hydrogen or, after subsequent introduction ofprotecting groups, R_(a)′ and R_(c)′ are each independently of the otherhydrogen or a protecting group, with the proviso that at least one ofthe two radicals is a protecting group, or R_(a)′ and R_(c)′ togetherare a bridging hydroxy-protecting group; and that compound is thenreduced as described above under (1) to form an amino compound offormula VI, as defined above, which can then be used further asdescribed above.

The invention relates also to a process for the preparation of the keyintermediate of formula I as defined above.

For that purpose, a compound of formula XI

wherein R_(a) is a hydroxy-protecting group (or, less preferred becausethe ee is then lower, hydrogen) and R_(b) is a carboxy-protecting group,is converted into the corresponding compound of formula I using areagent that introduces the radical X.

The compound of formula XI is in turn advantageously prepared byhydrolysing a compound of formula XII

wherein R_(a) is a hydroxy-protecting group (or, less preferred becausethe ee is then lower, hydrogen), R_(b) is a carboxy-protecting group andR_(d) is hydrocarbyl, by means of an enantioselective catalyst(preferably by hydrolysis using a biocatalyst) with removal of theradical R_(d), the corresponding compound of formula XI being obtaineddirectly.

The compound of formula XII is advantageously obtained by reacting aglutaric acid derivative of formula XIII

wherein R_(b) and R_(d) are as defined for compounds of formula XII, byintroduction of a hydroxy-protecting group using the correspondingreagent suitable for the introduction of the protecting group. Examplesof hydroxy protecting groups are given by T. W. Greene et al. in‘Protective Groups in Organic Chemistry’, John Wiley, New York, 2^(nd)edition, 1991, p 88 ff.

The invention relates also to new individual steps of the processesdescribed above, to new combinations of individual steps and to newintermediate compounds.

Unless indicated to the contrary, the general terms (including thereactions and reaction conditions) used hereinabove and hereinbelowpreferably have the following meanings—these specific definitions anddescriptions of reactions can be used independently of one anotherinstead of the general terms mentioned hereinabove and hereinbelow,resulting in preferred embodiments of the invention:

The prefix “-lower” or “lower” indicates that the radical in questioncontains preferably up to 7 carbon atoms, especially up to 4 carbonatoms. Lower alkyl is therefore preferably C₁-C₇-alkyl, especiallyC₁-C₄alkyl, and may be unbranched or branched one or more times, insofaras possible. Unsaturated radicals, such as alkenyl or alkynyl, have atleast two carbon atoms, preferably from 2 to 7, especially from 3 to 7,more especially 3 or 4.

In the processes mentioned hereinabove and hereinbelow, it is possibleat any stage, even where not explicitly mentioned, for one or more orall of the protecting groups present in the compounds of formulae I toXIX in question to be removed or for one or more or all of thefunctional groups that are not to participate in the reaction, or thatwould interfere with the reaction, to be converted into protected groupsby the introduction of suitable protecting groups (especiallyhydroxy-protecting groups and/or carboxy-protecting groups).

The protection of functional groups by such protecting groups, suitablereagents for their introduction, suitable protecting groups andreactions for their removal will be familiar to the person skilled inthe art. Examples of suitable protecting groups can be found in standardworks, such as J. F. W. McOmie, “Protective Groups in OrganicChemistry”, Plenum Press, London and New York 1973, in T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition,Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross andJ. Meienhofer), Academic Press, London and New York 1981, in “Methodender organischen Chemie”, Houben-Weyl, 4^(th) edition, Vol. 15/l, GeorgThieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit,“Aminosauren, Peptide, Proteine”, Verlag Chemie, Weinheim, DeerfieldBeach, and Basel 1982, and/or in Jochen Lehmann, “Chemie derKohlenhydrate: Monosaccharide and Derivate”, Georg Thieme Verlag,Stuttgart 1974.

Suitable hydroxy-protecting groups are especially selected from those ofthe acyl or ester type, e.g. lower alkanoyl, such as formyl, acetyl orisobutyroyl, benzoylformyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,phenylacetyl, p-phenylacetyl, diphenylacetyl,2,6-dichloro-4-methylphenoxyacetyl,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetyl,2,4-bis(1,1-dimethylpropyl)phenoxyacetyl, chlorodiphenylacetyl,3-phenylpropionyl, 4-azidobutyroyl, 4-methylthiomethoxybutyroyl,(E)-2-methyl-2-butenoyl, 4-nitro-4-methylpentanoyl, 4-pentenoyl,4-oxopentanoyl, 4,4-(ethylenedithio)pentanoyl,5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy)laevulinyl, pivaloyl,crotonoyl, monosuccinoyl, benzoyl, p-phenylbenzoyl,2,4,6-trimethylbenzoyl, 2-(methylthiomethoxymethyl)benzoyl,2-(chloroacetoxymethyl)benzoyl, 2-[(2-chloroacetoxy)ethyl]benzoyl,2-[(2-benzyloxy)ethyl]benzoyl, 2-[2-(4-methoxybenzyloxy)ethyl]benzoyl,2-iodobenzoyl, o-(dibromomethyl)benzoyl, o-(methoxycarbonyl)benzoyl,2-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, alkoxycarbonyl, such asmethoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl,methoxymethylcarbonyl, 9-fluorenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl,1,1-dimethyl-2,2,2-trichloroethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl,2-(triphenylphosphonio)ethoxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, p-nitrophenoxycarbonyl, benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,dansylethoxycarbonyl, 2-(4-nitrophenyl)ethoxycarbonyl,2-(2,4-dinitrophenyl)ethoxycarbonyl, 2-cyano-1-phenylethoxycarbonyl,S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,3′,5′-dimethoxybenzoinyloxycarbonyl, 2-methylthiomethoxyethoxycarbonyl,N-phenylcarbamoyl, dimethylethylphosphinothiolyl, methyldithiocarbonyl;N,N,N′,N′-tetramethylphosphorodiamidoyl, sulfonyl, methanesulfonyl,benzenesulfonyl, toluenesulfonyl, 2-[(4-nitrophenyl)ethyl]sulfonyl,allylsulfonyl, 2-formylbenzenesulfonyl, nitroxy, or protecting groups ofthe ether type, such as methyl, substituted methyl, preferably loweralkoxymethyl, especially methoxymethyl (MOM), methylthiomethyl,(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,p-methoxybenzyloxymethyl, p-nitrobenzyloxymethyl, guaiacolmethyl,tert-butoxymethyl, 4-pentenyloxymethyl, silyloxymethyl, loweralkoxy-lower alkoxymethyl, especially 2-methoxyethoxymethyl (MEM),2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)-ethoxymethyl ormenthoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxythiopyranyl, 1-methoxycyclohexyl,4-methoxytetrahydrothiopyranyl,S,S-dioxy-4-methoxytetrahydrothiopyranyl,1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl;substituted ethyl, such as 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl,1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl,1,1-dianisyl-2,2,2-trichloroethyl,1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl,2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tert-butyl; allyl orpropargyl, substituted phenyl ethers, such as p-chlorophenyl,p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl or2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, benzyl, substitutedbenzyl, such as p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, e.g. p-bromobenzyl, 2,6-dichlorobenzyl,p-cyanobenzyl, p-phenylbenzyl, 2,6-difluorobenzyl, p-azidobenzyl,4-azido-3-chlorobenzyl, 2-trifluoromethylbenzyl orp-(methylsulfinyl)benzyl, 2- or 4-picolyl, 3-methyl-2-picolyl,2-quinolinylmethyl, 1-pyrenylmethyl, diphenylmethyl,p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl),4,4′,4″-tris(laevulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,4,4′-dimethoxy-3″-[N-(imidazolylmethyl)]trityl,4,4′-dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl,4-(17-tetrahydrobenzo[a,c,g,i]fluorenylmethyl)-4′,4″-dimethoxytrityl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, S,S-dioxo-benzoisothiazolyl; of the silyl ethertype, such as tri-lower alkylsilyl, e.g. trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, tert-butyldimethylsilyl ordi-tert-butylmethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl,diphenylmethylsilyl, tris(trimethylsilyl)silyl,(2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl,tert-butylmethoxyphenylsilyl or tert-butoxydiphenylsilyl.

Bridging protecting groups can likewise be used where a moleculecontains two hydroxy groups (for example bridging hydroxy-protectinggroups formed by R_(a) and R_(c) or R_(a)′ and R_(c)′ together) or ahydroxy-protecting group and a carboxy group (for example bridgingprotecting groups formed by R_(a) and R_(b) or R_(a)′ and R_(b) in themolecules of the corresponding formulae mentioned hereinabove andhereinbelow in which those radicals are present).

A bridging hydroxy-protecting group (especially one formed by R_(a)′ andR_(c)′) is preferably selected from methylene, ethylidene,tert-butylmethylidene, 1-tert-butylethylidene, 1-phenylethylidene,1-(4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene,vinylmethylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene,benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene,3,4-dimethoxybenzylidene, 2-nitrobenzylidene, 4-nitrobenzylidene,mesitylene, phenyl-(1,2-bis(methylenyl)), methoxymethylene,ethoxymethylene, dialkylsilylene, such as tert-butylsilylene,1,3-(1,1,3,3-tetraisopropyldisiloxanylidene),1,1,3,3-tetra-tert-butoxydisiloxanylidene, —C(═O)—, ethylboronyl(—(H₃C—CH₂)B—), phenylboronyl (-(phenyl)B—), o-acetamidophenylboronyl orespecially isopropylidene.

Carboxy-protecting groups are especially ester-forming, enzymaticallyand/or chemically removable protecting groups, preferably enzymaticallyand/or chemically removable protecting groups, such as heptyl,2-N-(morpholino)ethyl, cholinyl, methoxyethoxyethyl or methoxyethyl; orthose which are primarily chemically removable, e.g. alkyl, such aslower alkyl, especially methyl, ethyl, substituted lower alkyl (exceptfor benzyl and substituted benzyl), such as substituted methyl,especially 9-fluorenylmethyl, methoxymethyl, methoxyethoxymethyl,methylthiomethyl, 2-(trimethylsilyl)ethoxym ethyl, benzyloxymethyl,pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl,1,3-dithianyl-2-methyl, dicyclopropylmethyl, acetonyl, phenacyl,p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl, desyl,carbamidomethyl, p-azobenzenecarboxamidomethyl, N-phthalimidomethyl or4-picolyl, 2-substituted ethyl, especially 2-iodo-, 2-bromo- or2-chloro-ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-methylthioethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(p-toluenesulfonyl)ethyl, 2-(2′-pyridyl)ethyl,2-(p-methoxyphenyl)ethyl, 2-(diphenylphosphino)ethyl,1-methyl-1-phenylethyl, 2-(4-acetyl-2-nitrophenyl)ethyl or 2-cyanoethyl,tert-butyl, 3-methyl-3-pentyl, 2,4-dimethyl-3-pentyl or ω-chloro-loweralkyl, especially 4-chlorobutyl or 5-chloropentyl, cyclopentyl,cyclohexyl, lower alkenyl, especially allyl, methallyl,2-methylbut-3-en-2-yl, 3-methylbut-2-enyl or 3-buten-1-yl, substitutedlower alkenyl, especially 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl orα-methylcinnamyl, lower alkynyl, such as prop-2-ynyl, phenyl,substituted phenyl, especially 2,6-dialkylphenyl, such as2,6-dimethylphenyl, 2,6-diisopropylphenyl,2,6-di-tert-butyl-4-methylphenyl, 2,6-di-tert-butyl-4-methoxyphenyl,p-(methylthio)phenyl or pentafluorophenyl, benzyl, substituted benzyl,especially triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl,9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl,1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl,2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl,p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl,4-sulfobenzyl, 4-azidomethoxybenzyl,4-{N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl,piperonyl or p-polymer-benzyl, tetrahydropyranyl, tetrahydrofuranyl, orsilyl radicals, such as tri-lower alkylsilyl, especially trimethylsilyl,triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl ordi-tert-butylmethylsilyl, or phenyl-di-lower alkylsilyl, such asphenyldimethylsilyl; alternatively a carboxy group can also be protectedin the form an oxazolyl, 2-alkyl-1,3-oxazolinyl,4-alkyl-5-oxo-1,3-oxazolidinyl or2,2-bistrifluoromethyl-4-alkyl-5-oxo-1,3-oxazolidinyl radical.

Amide-protecting groups are especially allyl, tert-butyl, N-methoxy,N-benzoyloxy, N-methylthio, triphenylmethylthio,tert-butyldimethylsilyl, triisopropylsilyl, 4-(methoxymethoxy)phenyl,2-methoxy-1-naphthyl, 9-fluorenyl, tert-butoxycarbonyl,N-benzyloxycarbonyl, N-methoxy- or N-ethoxy-carbonyl, toluenesulfonyl,N-buten-1-yl, 2-methoxycarbonylvinyl, or especially alkyl, such as loweralkyl, or more especially substituted alkyl, especially benzyl, benzylsubstituted by one or more radicals selected from lower alkoxy, such asmethoxy, lower alkanoyloxy, such as acetoxy, lower alkylsulfinyl, suchas methylsulfinyl, dicyclopropylmethyl, methoxymethyl, methylthiomethyland N-benzoyloxymethyl; or bis(trimethylsilyl)methyl,trichloroethoxymethyl, tert-butyldimethylsilyloxymethyl,pivaloyloxymethyl, cyanomethyl, benzyl, 4-methoxybenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-acetoxy-4-methoxybenzyl,o-nitrobenzyl, bis(4-methoxyphenyl)phenylmethyl,bis(4-methylsulfinylphenyl)methyl, pyrrolidinomethyl, diethoxymethyl,1-methoxy-2,2-dimethylpropyl or 2-(4-methylsulfonyl)ethyl.

It is characteristic of protecting groups that they are simple to remove(that is to say without undesirable secondary reactions taking place),for example by solvolysis, reduction, photolysis or alternatively underconditions analogous to physiological conditions, for exampleenzymatically.

The person skilled in the art will know which protecting groups can beused for which reactions and compounds of formulae I to XIX. In the caseof compounds of formula I that are to be converted into compounds offormula III, it is advisable to use especially those protecting groupswhich would not also react during the (Friedel-Crafts-analogous)reaction, that is to say without aryl radicals, such as phenyl radicals.Hydroxy-protecting groups R_(a) and R_(a)′ are especially those whichcan be selectively introduced and removed, more especially those whichare not removed during the conversion of compounds of formula XII. Hereit is especially advisable to use hydroxy-protecting groups that do notcontain too strongly electronegative substituents, more especially loweralkanoyl, such as acetyl, lower alkoxy-lower alkanoyl, such asmethoxyacetyl, or protecting groups of the substituted methyl type,especially lower alkoxymethyl, more especially methoxymethyl (MOM), orlower alkoxy-lower alkoxymethyl, especially 2-methoxyethoxymethyl (MEM).

Acyloxy in formula I or III is especially the radical of an organiccarboxylic or sulfonic acid having from 1 to 24 carbon atoms,unsubstituted or substituted by one or more radicals, especially from 1to 3 radicals, preferably selected from lower alkoxy, halogen, nitro,lower alkoxycarbonyl, phenyl, phenyl-lower alkyl, phenyloxy, loweralkanoyloxy, benzoyloxy, di-lower alkyl-amino, N-phenyl-loweralkyl-N-lower alkyl-amino, N,N-di(phenyl-lower alkyl)amino, carbamoyl,thiocarbamoyl, sulfamoyl and cyano, and saturated or partially or fullyunsaturated, and is preferably the radical of an alkanecarboxylic acidor haloalkanecarboxylic acid, especially lower alkanoyl, of anarylcarboxylic acid, especially benzoic acid, or halo-loweralkanesulfonyl, such as trifluoromethanesulfonyl; or, in the case of acompound of formula I, a radical of formula I′

wherein R_(a) and R_(b) are as defined for compounds of formula I (thecompound of formula I is then a symmetric anhydride (obtainable, forexample, by reaction of the acid of formula I (OH instead of X) in thepresence of a lower alkanecarboxylic acid anhydride, such as aceticanhydride, in the presence of catalytic amounts of acid)).

Activated hydrocarbyloxy or hydrocarbylthio is preferably unsubstitutedor substituted lower alkyloxy, unsubstituted or substituted aryloxy(preferably having from 6 to 12 ring atoms) or unsubstituted orsubstituted heterocyclyloxy (preferably an unsaturated, fully orpartially saturated mono- or bi-cyclic ring system having from 4 to 12ring atoms and up to three hetero atoms selected from nitrogen, sulfurand oxygen) and is especially lower alkyloxy substituted in the1-position by esterified carbonyl, such as lower alkoxycarbonyl, cyanoor by phenylcarbonyl, especially lower alkoxycarbonylmethoxy, such asethoxycarbonylmethoxy, cyanomethoxy or phenacyloxy (Ph-CO—CH₂—O—),tert-butylthio, N-benzotriazolyloxy, N-succinimidyloxy, pyridyloxy orpyridylthio, especially 2-pyridyloxy or more especially 2-pyridylthio,or electronegatively substituted aryloxy, such as p-nitrophenyloxy,2,4-dinitrophenyloxy, pentafluorophenyloxy or 2,4,5-trichlorophenyloxy.

The reaction of the key intermediate of formula (I) with an ethylene offormula II is effected preferably in the presence of a Lewis acid, suchas FeCl₃, SbCl₅, SnCl₄, BF₃, TiCl₄, ZnCl₂ or especially aluminiumchloride (AlCl₃), preferably in a suitable solvent, especially ahalogenated hydrocarbon, such as chloroform, methylene chloride orethylene chloride, at preferred temperatures of from −10° C. to thereflux temperature, especially from 0 to 30° C.

Any hydroxy-protecting groups R_(a) can then, if necessary, be removedselectively from the compound of formula III by customary methods,especially by the methods described in the standard works mentionedabove.

“Selectively” means especially enzymatically. In particular, loweralkanoyl, such as acetyl, is removed enzymatically, for example byesterases, such as pig's liver esterase, in suitable buffers, such asphosphate buffer, at preferred pH values of from 5 to 9, especially from6 to 8. Further possible enzymes and reaction conditions will be foundbelow under the definition of biocatalysts for the hydrolysis. Loweralkoxymethyl, such as MOM, or lower alkoxy-lower alkoxymethyl, such asMEM, is removed by chemical standard methods.

The reaction of a compound of formula III wherein Y_(a) is hydrogen andX_(a) is halogen, while R_(a) and R_(b) are as defined for compounds offormula III, with a salt of hydrazoic acid to form a compound of formulaIV, as defined above, or of a compound of formula Va wherein X_(a) ishalogen, especially iodine or especially chlorine or bromine, whileR_(a) and R_(b) are as defined for compounds of formula II, with a saltof hydrazoic acid to form a compound of formula V, as defined above, ispreferably carried out with such a salt in the presence of acomplex-forming agent for the metal cation, especially with an alkalimetal azide, such as sodium or potassium azide, in the presence of acrown ether, especially 18-crown-6-ether, in a suitable solvent,preferably an aprotic solvent, such as a di-lower alkyl-loweralkanoylamide, e.g. dimethylformamide or dimethylacetamide, or adi-lower alkyl sulfoxide, e.g dimethyl sulfoxide, or the like. Thereaction can alternatively be carried out under conditions of phasetransfer catalysis, i.e. in the presence of two-phase systems, such aswater/organic solvent (such as halogenated hydrocarbons, e.g. methylenechloride, chloroform or dichloroethane), in the presence of lipophilicquaternary ammonium salts, such as hydrogen sulfate or chloride, e.g.tetrabutylammonium hydrogen sulfate, Aliquat 336, Adogen 464 (bothconsisting primarily of methyltrioctylammonium chloride), preferablytetra-lower alkylammonium bromide or iodide, such as tetrabutylammoniumbromide or iodide or the like, the base being present in the aqueousphase.

The diastereoselective reduction of the obtainable azido compound offormula IV (if necessary after removal of the hydroxy-protecting groupR_(a), preferably as described above for the removal of thehydroxy-protecting group R_(a) from a compound of formula III) to form acompound of formula V; of a compound of formula III (if necessary afterremoval of the hydroxy-protecting group R_(a) (from a compound offormula II) as described above) to form a compound of formula V; in eachcase as defined above and below, is then preferably carried out in achelate-controlled manner, there being used as chelate-forming agentpreferably a di-lower alkyl borinic acid lower alkyl ester, especiallydiethyl borinic acid ethyl ester. The reduction of the chelatedβ-hydroxyketone of formula III is then effected with a complex hydride,preferably with an alkali metal borohydride, especially with sodiumborohydride. As solvent there are preferably used ethers, such as cyclicethers, especially tetrahydrofuran, and/or alcohols, such as loweralkanols, e.g. methanol, the preferred reaction temperatures being from−80 to −30° C., especially from −78 to −40° C.

In addition, preferred is the diasteroselective reduction of compound offormula III, wherein X_(a) is halogen, especially chlorine or bromine ormore especially chlorine, and Y_(a) is hydrogen, R_(a) is hydrogen andR_(b) is a carboxy-protecting group; is reacted with hydrogen in thepresence of an alkali metal salt or alkaline-earth metal salt and aheterogeneous platinum catalyst to form a syn-diol compound of formulaVa

wherein X_(a) is halogen, especially chlorine or bromine or moreespecially chlorine, and R_(a)′ and R_(c)′ are as defined for compoundsof formula V and R_(b) is a carboxy-protecting group. Preferred salt isan alkaline-earth metal salt, most preferred is a magnesium salt, andespecially preferred is magnesium acetate. Customary, thisdiasteroselctive reduction is carried under pressure between 1 to 100bar at temperatures between 0 to 100° C. Most preferably the reductionis carried out using platinum on carbon catalyts together with magnesiumacetate with hydrogen under a pressure of 6 to 60 bar at temperaturesbetween 10 to 60° C.

In a broader embodiment of the invention it is also preferred to usealternative reducing agents, such as sodium cyanoborohydride, but thisresults in lower diastereoselectivity and is therefore less preferred.

When it is desirable or necessary subsequently to introduce a protectinggroup into the compound of formula V or Va (R_(a)′, R_(c)′ or R_(a)′ andR_(c)′ as protecting group, especially R_(a)′ and R_(c)′ together as abridging protecting group), this is carried out under standardconditions, preferably as described in the above-mentioned standardworks.

The bridging protecting group formed by R_(a)′ and R_(c)′ together,preferably as indicated above, especially the isopropylidene protectinggroup, is especially introduced by standard methods, preferably asdescribed in the standard works mentioned above, in the case of theisopropylidene protecting group especially by reaction with acetone or,preferably, with a di-lower alkoxypropane, such as dimethoxypropane, inthe presence of copper(II) sulfate, zinc chloride or, preferably, anacid, such as sulfuric acid or especially an organic sulfonic acid, suchas an arylsulfonic acid (wherein aryl has especially from 6 to 10 ringatoms, e.g. naphthyl or phenyl, and is unsubstituted or mono- orpoly-substituted, especially up to tri-substituted, especially by loweralkyl, such as methyl), preferably toluenesulfonic acid, or with a loweralkyl isopropenyl ether, such as ethyl isopropenyl ether, in thepresence of an arylsulfonic acid. As preferred solvents there are usedaprotic solvents, such as ethers, especially cyclic ethers, moreespecially tetrahydrofuran, or carboxylic acid amides, such as di-loweralkyl-lower alkanoylamides, e.g. dimethylformamide. The preferredreaction temperatures are in the range of from 0 to 80° C., especiallyfrom 20 to 30° C.

The reduction of the azide of formula V to the amine of formula VI ispreferably carried out with a complex hydride, or with tributyltin; orpreferably by catalytic hydrogenation, for example with hydrogen andplatinium or palladium on activated carbon, preferably in an alcohol,such as methanol or ethanol, at hydrogen pressures of from 0.5 to 20bar, for example at 10 bar, at temperatures of from 0 to 50° C.,especially from 15 to 35° C. Alternatively, the reduction can beeffected by reaction with a tertiary phosphine and subsequent treatmentwith water (Staudinger reduction).

The reaction of a compound of formula III wherein Y_(a) is hydrogen orhalogen, especially iodine or more especially chlorine or bromine, andX_(a) is halogen, while R_(a) and R_(b) are as defined for compounds offormula II, in the presence of a base, with elimination of hydrohalicacid HX, to form an olefin of formula VII is preferably carried out inthe presence of a base selected from a nitrogen base, especially atertiary amine, such as a tri-lower alkylamine, e.g. triethylamine,pyridine, quinoline, di-lower alkylaniline, such as dimethylaniline,dicyclohexylethylamine, amidines, such as1,5-diazabicyclo[4.3.0]non-5-ene or 1,8-diazabicyclo[5.4.0]undec-7-ene,or a different base selected from alkali metal hydroxides, metalcarbonates or hydrogen carbonates, alkali metal alcoholates in thecorresponding alcohol or inert solvents, such as dimethyl sulfoxide,e.g. potassium tert-butyl alcoholate, alkali metal amides in inertsolvents or the like. Where a solvent is used, preferred solvents areethers, such as diethyl ether, di-lower alkyl-lower alkanoylamides, suchas dimethyl- or diethylformamide or -acetamide, or the solvents alreadymentioned. The preferred reaction temperatures are from −20° C. to thereflux temperature of the reaction mixture in question, preferably from−10 to 30° C.

The reaction with an iodide salt to form the corresponding compound offormula VII wherein Y_(a)′ is iodine is then preferably effected with ametal iodide, especially an alkali metal iodide, such as sodium iodide,in the presence of a Lewis acid, especially aluminium chloride, in asuitable solvent, preferably a ketone, such as acetone, at preferredtemperatures in the range of from 0 to 50° C., especially from 20 to 30°C.

The reduction of a compound of formula VII, if necessary after removalof the hydroxy-protecting group R_(a) by methods described in thestandard works, preferably as described for the removal ofhydroxy-protecting groups R_(a) from the compound of formula II, is theneffected diastereoselectively, under conditions analogous to thosedescribed for the diastereoselective reduction of compounds of formulaIV, to form the corresponding syn-diol compound of formula VIII.

If necessary, the protecting groups R_(a)′ and/or R_(c)′ or a bridgingprotecting group formed by R_(a)′ and R_(c)′ are introduced into thatcompound under conditions analogous to those described for theintroduction of protecting groups in a compound of formula V.

The oxidative cleavage of a compound of formula VIII to form an aldehydeof formula IX is then carried out preferably by ozonolysis andsubsequent working-up of the primary product with a suitable reducingagent, especially triphenylphosphine, dimethylsulfide or zinc/aceticacid, there being used as solvent preferably a halogenated hydrocarbon,especially methylene chloride, and the preferred temperatures for thereaction with ozone being from −80 to −50° C., preferably from −78 to60° C., and for the subsequent working-up from −20 to 50° C., preferablyfrom 20 to 30° C.; or by reaction with Os(VIII), preferably OsO₄ (usedas such, in catalytic amounts in the presence of stoichiometric amountsof N-methylmorphine-N-oxide (NMO) or peroxides, such as hydrogenperoxide, or prepared in situ, for example by oxidation of catalyticamounts of K₂OsO₄ with stoichiometric amounts of NMO) or withpermanganates, preferably potassium permanganate, the reaction withOs(VIII) or permanganates preferably being effected in a polar solvent,such as an alcohol, e.g. ethanol, and/or water, if desired in thepresence of inert salts, such as magnesium sulfate, at preferredtemperatures of from −20 to 40° C., for example from −10 to 20° C.; theoxidative cleavage of the intermediate diol (not described) is thencarried out with an alkali metal periodate, especially NaIO₄ (in awater-containing medium), or with H₅IO₆ (in a water-containing oranhydrous medium), or less preferably with lead tetraacetate (in ananhydrous medium).

The reaction of an aldehyde of formula IX with iodoform (CHI₃),diiodomethane or methyl iodide to form an iodine compound of formula Xis carried out especially in the presence of a chromium(II) halide,especially chromium dichloride, under protective gas in a suitablesolvent, such as an ether, especially tetrahydrofuran, at preferredtemperatures of from −10 to 50° C., especially from −5 to 30° C.

The reaction for the preparation of a compound of formula XI to form thecorresponding compound of formula I is preferably effected undercustomary conditions, there being used as reagent for introducing aradical X especially an acid anhydride or an acid halide, preferably aninorganic acid halide, more especially a phosphorus trihalide,phosphorus pentahalide or thionyl halide, such as phosphoryl chloride,phosphoryl bromide, phosphorus trichloride, phosphorus tribromide,phosphorus pentachloride, phosphorus pentabromide, thionyl chloride orthionyl bromide, a symmetric anhydride of a lower alkanesulfonic acidhalogenated at the α-carbon atom, such as trifluoromethanesulfonicanhydride, or an acid chloride or a symmetric anhydride of an organiccarboxylic acid, especially an oxalyl halide, such as oxalyl chloride orbromide, the reaction being carried out in the absence or preferablypresence of a (preferably polar) solvent or solvent mixture, especiallyin a halogenated hydrocarbon, preferably methylene chloride, in theabsence or presence of an acid amide, especially a di-lower alkyl-loweralkanoic acid amide, such as dimethylformamide, at preferredtemperatures of from −20° C. to the reflux temperature of the reactionmixture in question, preferably from −10 to 50° C.

Preference is given to lower alkyl, especially methyl or more especiallyethyl, or lower alkoxy-lower alkyl, especially methoxymethyl.

The preparation of a compound of formula XI is preferably effected withremoval of the hydrocarbyl radical R_(d) in the presence of anenantioselective catalyst, especially a biocatalyst.

As biocatalysts for the hydrolysis there are suitable cells or rupturedcells with the enzymes mentioned below, or especially enzymes as such,preferably esterases, lipases and proteases (peptidases or amidases, seeU. T. Bornscheuer and R. T. Kazlauskas, in: Hydrolases in OrganicSynthesis, Wiley-VCH, 1999, pages 65-195, ISBN 3-527-30104-6). Commonrepresentatives of those classes of enzyme are especially animalesterases (e.g. pig's liver esterase=PLE, pig's pancreas esterase=PPL),esterases from microorganisms or fungi (B. subtilis esterase, Pichiaesterases, yeast esterases, Rhizopus sp. esterases (RML, ROL),Penicillium sp. esterases, G. candidum (GCL), H. lanuginosa (HLL),Candida sp. (CAL-A, CAL-B, CCL), Aspergillus sp. (ANL), Pseudomonas sp.(PCL, PFL) and the like), and also proteases, e.g. subtilisin,thermitase, chymotrypsin, thermolysin, papain, aminoacylases, penicillinamidases, trypsin or the like, to name only a few. The person skilled inthe art will be familiar with further suitable enzymes, and the enzymesthat can be used are not limited to those mentioned in the above list.Such enzymes can be obtained in the form of crude isolates and/or inpurified form from natural sources and/or from recombinantmicroorganisms by means of modern cloning procedures via overexpression,amplification or the like. Commercially available enzymes are especiallypreferred. The enzymes can be present as such or immobilised or adsorbedon carriers, for example on silica gel, kieselguhr, such as Celite®,Eupergit® (Röhm & Haas, Darmstadt, Germany) or the like, or used in theform of “CLECs” (cross-linked enzymes), such as are available from ALTUSBIOLOGICS, the scope for use extending beyond the list given, as theperson skilled in the art will know (see U. T. Bornscheuer and R. T.Kazlauskas, in: Hydrolases in Organic Synthesis, Wiley-VCH, 1999, pages61-64, ISBN 3-527-30104-6; K. Faber in: Biotransformation in OrganicChemistry, Springer 1997, Third Edition, pages 345-357, ISBN3-540-61688-8; H. J. Rehm, G. Reed in: Biotechnology, VCH 1998, SecondEdition, pages 407-411). The enzymes can be used in pure organicsolvents, e.g. liquid hydrocarbons, such as hexane, toluene or benzene,liquid ethers, such as diethyl ether, methyl tert-butyl ether ortetrahydrofuran, liquid halogenated hydrocarbons, such as methylenechloride, water or aqueous buffer solutions, in mixtures of thosesolvents, for example mixtures of one or more thereof with water oraqueous buffer solutions. The aqueous solution is preferably buffered,pH 5-9, it being possible to use customary buffer systems (see e.g. K.Faber in: Biotransformation in Organic Chemistry, Springer 1997, ThirdEdition, p. 305; or U. T. Bornscheuer and R. T. Kazlauskas, in:Hydrolases in Organic Synthesis, Wiley-VCH, 1999, pages 61-65). The pHis preferably kept substantially constant during the reaction. Mostsuitable for this purpose is an automatic titrator having a standardisedacid or base solution, or manual titration. The reaction temperature ispreferably in the range from 10 to 50° C., especially from 25 to 40° C.The amount of biocatalyst used and the concentrations of the reagentscan be dependent upon the substrate and the reaction conditions(temperature, solvent etc.) selected in each case, as will be known tothe person skilled in the art. There are preferably used commerciallyavailable enzymes (for example from Fluka, Sigma, Novo Nordisk, Amano,Roche and the like) or those listed in the current literature (see e.g.H.-J. Rehm, G. Reed in: Biotechnology, VCH 1998, 2^(nd) Edition, pages40-42). Especially preferred for the preparation of enantiomericallypure compounds is α-chymotrypsin in phosphate buffer, especially at pH7.0.

Unless otherwise indicated, halogen is preferably fluorine, chorine,bromine or iodine.

Wherever solvents are mentioned hereinabove and hereinbelow it is alsopossible, where expedient and possible, for mixtures of two or more ofthe mentioned solvents to be used.

The person skilled in the art will know that for certain reactions suchsolvents or solvent mixtures must be used in anhydrous (absolute) formand that, if necessary, also the reaction vessels used must have drysurfaces.

Where necessary, the said reactions are carried out in the absence ofoxygen, and often also in the absence of carbon dioxide and/oratmospheric moisture, for example under protective gas, such as argon ornitrogen.

Where possible, the starting compounds and intermediate compounds canalso be used in the form of salts, obtained in the form of salts orconverted into salts in accordance with customary processes, for examplein the case of carboxy compounds into the corresponding metal salts,such as alkali metal salts, e.g. sodium or potassium salts, or alkalineearth metal salts, such as calcium salts, or salts with nitrogen bases,such as ammonium, tri-lower alkylammonium, pyridinium salts or the like.Where salt formation is possible, any reference to any of the compoundsshould be understood as also including the corresponding salts.

In addition to the solvents already mentioned, it is also possible touse other suitable solvents, where expedient and possible for thereaction in question. Such solvents can be selected, for example, fromthe following list: water, esters, e.g. lower alkyl-lower alkanoates,such as diethyl acetate, ethers, e.g. aliphatic ethers, such as diethylether, or cyclic ethers, such as dioxane or tetrahydrofuran, liquidaromatic hydrocarbons, such as benzene or toluene, alcohols, such asmethanol, ethanol or 1- or 2-propanol, nitrites, such as acetonitrile,halogenated hydrocarbons, such as dichloromethane, chloroform orethylene chloride, acid amides, such as dimethylformamide, bases, e.g.heterocyclic nitrogen bases, such as pyridine, carboxylic acids, such aslower alkanecarboxylic acids, e.g. acetic acid, carboxylic acidanhydrides, e.g. lower alkanoic acid anhydrides, e.g. acetic anhydride,cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of such solvents or other solvents, e.g. aqueoussolutions. Such solvents and solvent mixtures can also be used inworking-up, e.g. by chromatography or partition. Any mention of solventsor eluants hereinabove and hereinbelow should be understood as includingalso mixtures of such solvents or eluants.

The other compounds, especially of formula II, are known, can beprepared according to methods known per se and/or are commerciallyavailable.

PREFERRED EMBODIMENTS OF THE INVENTION

Preferred aspects of the invention can be found in the claims which areincorporated herein by reference.

Hereinabove and hereinbelow, the radicals in compounds of formulae I toXIX have the meanings given hereinabove and hereinbelow (especially thespecific meanings mentioned for certain reaction variants or methods),and the reaction conditions are in each case as defined hereinabove orhereinbelow, preferably as the preferred reaction conditions:

Preference is given to a process for the preparation of statinderivatives which comprises the preparation of a compound of formula I,as defined hereinabove and hereinbelow, from a compound of formula XI,preferably such a process for the preparation of a compound of formulaI; the compound of formula XI in turn preferably being prepared from acompound of formula XII which, in turn, is preferably prepared from acompound of formula XIII.

Also preferred is a process for the preparation of statin derivatives,especially of statin precursors of formulae VI, IX and/or X, whichcomprises the reaction of a key intermediate of formula I. Compound offormula I reacts with an ethylene of formula II to form a keto compoundof formula III, which is reacted in accordance with one of methods (1),(2) and (3), method (1) comprising reaction to form an azido compound offormula IV, which is then converted into a syn-diol compound of formulaV and then into an amino compound of formula VI; or according to method(2) is converted into an olefin of formula VII; or according to method(3) is converted into a compound of formula Va, which is then convertedinto an azide of formula V, which is then converted into an aminocompound of formula VI; and preferably the compound of formula VIIobtained according to method (2), unless used directly for thepreparation of statin derivatives (if desired after conversion into thecorresponding compound wherein Y_(a)′ is iodine), is reduced to form asyn-diol compound of formula VIII, which in turn is then cleavedoxidatively to form an aldehyde of formula IX, which, if desired, isthen converted into an iodine compound of formula X.

Also preferred is a process for the preparation of statin derivatives,especially of compounds of formula VI, which comprises the reaction of acompound of formula I with an ethylene of formula II to form a compoundof formula II, conversion thereof into an azide of formula IV, reductionto a compound of formula V and conversion thereof into an amino compoundVI; or especially conversion thereof into a syn-diol of formula Va,subsequent conversion thereof into a compound of formula V andconversion thereof into an amino compound VI.

Preference is given also to a process for the preparation of statinderivatives, especially of statin precursors of formula VII, preferablyof formula VIII, especially of formula IX, more especially of formula X,which comprises the reaction of the key intermediate of formula I withan ethylene of formula II to form a keto compound of formula III andreaction thereof to form a compound of formula VII; which is preferablyreduced diastereoselectively for the preparation of a compound offormula VIII, which is especially cleaved oxidatively for thepreparation of a compound of formula IX, which is especially convertedinto an iodine compound of formula X.

Also preferred is a process for the preparation of statin derivatives,especially of statin precursors of formula VII, preferably of formulaVIII, especially of formula IX, more especially of formula X, whichcomprises the reaction of the key intermediate of formula I with acompound of formula III to form a compound of formula VII; which ispreferably reduced diastereoselectively for the preparation of acompound of formula VIII, which is especially cleaved oxidatively forthe preparation of a compound of formula IX, which is especiallyconverted into an iodine compound of formula X.

In all the preferred embodiments, if necessary one or more or all of theprotecting groups present are removed or one or more or all of thefunctional groups that are not to participate in a reaction, or thatwould interfere with the reaction, are converted into protected groupsby the introduction of suitable protecting groups (especiallyhydroxy-protecting groups and/or carboxy-protecting groups); and, wheresalt-forming groups are present and the reaction in question is notimpaired, the compounds of formulae I to XIX may also be in salt form.

Of the compounds, the invention relates especially to those of formulaeI, III, IV, V, VII and VIII as such, especially those in which thesubstituents correspond to the radicals indicated in the respectiveExamples.

Special preference is given to the compounds 1d, 1e, 2a, 2b, 2c, 2d, 2e,2f, 3a, 3b, 3d, 3e, 4a, 4b, 6a, 6b, 6c, 6d, 6e, 6f, and Bb mentioned inthe Examples, especially each individual compound.

The present invention relates especially to the reaction steps and newintermediate compounds mentioned in the following Examples.

EXAMPLES

The following Examples serve to illustrate the invention but do notlimit the scope thereof.

Abbreviations Used:

-   Celite Celite®, filtration aid based on kieselguhr, trade mark of    Celite Corp., USA-   TLC thin-layer chromatography-   DMF dimethylformamide-   eq. equivalent-   h hour(s)-   Hünig's base N-ethyldiisopropylamine min minute(s)-   NMR nuclear magnetic resonance spectroscopy-   PLE pig's liver esterase-   m.p. melting point (° C.)-   THF tetrahydrofuran-   torr unit of pressure (mm mercury column); 1 torr corresponds to    0.1333 kPa

Unless otherwise indicated, the ratios of the components of eluantmixtures, solvent mixtures and the like are given in parts by volume(v/v).

Example 1 a) Precursor of formula Ba wherein R=ethyl, A=acetyl(diethyl-3-acetoxyglutaric acid)

54.0 g of diethyl-3-hydroxyglutaric acid (Fluka, Buchs, Switzerland) aredissolved at room temperature in 26.5 ml of pyridine and 27.4 ml ofacetic anhydride and the mixture is stirred for about 12 h until all thestarting material has reacted. The mixture is diluted with ethyl acetateand washed in succession with water, 1N hydrochloric acid, saturatedsodium hydrogen carbonate solution and saturated sodium chloridesolution. The organic phase is separated and dried over magnesiumsulfate. After evaporation of the organic solvent, 64.3 g ofNMR-spectroscopically pure acetate, the title compound, remain: ¹H-NMR(CDCl₃): 1.24 (t, 6H); 2.01 (s, 3H); 2.69 (d, 4H); 4.14 (q, 4H); 5.50(quin., 1H).

b) Compound of formula Ca wherein R=ethyl, A=acetyl(monoethyl-3(R)-acetoxyglutaric acid)

160 g of diethyl-3-acetoxyglutaric acid Ba are suspended at roomtemperature in 570 ml of distilled water, and 168 ml of 0.1M phosphatebuffer (pH 7) are added. After the addition of 2.7 g of α-chymotrypsin(Sigma, Sigma Chemie, Buchs, Switzerland), the mixture is stirredvigorously and maintained at pH 7.8 using a pH meter and pH stat(Metrohm) and 0.5N sodium hydroxide solution. When the theoreticalamount of hydroxide solution (1.3 litres) has been consumed, the mixtureis extracted with ethyl acetate. The aqueous phase is adjusted to pH 1with concentrated hydrochloric acid (conc. HCl) and then extracted withethyl acetate. Any cloudiness of the organic phase can be removed byfiltration over Celite. After evaporation of the organic phase, 131 g(97%) of semi-ester Ca remain: ¹H-NMR (CDCl₃): 1.25 (t, 3H); 2.03 (s,3H); 2.71 (d, 2H); 2.77 (d, 2H); 4.14 (q, 2H); 5.50 (quin., 1H).

c) Determination of the Enantiomeric Excess (ee) of the Monoacid Ca byMeans of the Amide Da (R=ethyl, A=acetyl)

150 mg of the monoacid Ca are reacted in accordance with the customarymethods of peptide coupling with 341 mg of(benzotriazol-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate, 246 mg of Hünig's base and 931 μl ofR-phenylethylamine (Fluka, Buchs, Switzerland) in 1.5 ml of DMF at roomtemperature. After customary extraction, 188 mg of amide Da areobtained. NMR spectroscopy indicates a diastereoisomeric ratio of 99:1on the basis of the shift difference between the two diastereoisomericacetates and accordingly a ratio of R to S of 99:1. HPLC analysis(column: Chiracel OJ 25 cm×0.46 cm (Daicel Chemical Industries, Ltd.,JP), n-hexane:ethanol=95:5, flow rate 1.2 ml/min, UV detection at 210nm) confirms the ratio of R to S as 98.8:1.2. ¹H-NMR (CDCl₃): 1.15 (t,3H); 1.35 (d, 3H); 1.85 and 1.87 (2×s, total 3H, ratio as 99:1); 2.47(m, 2H); 2.55 (dd, 1H); 2.65 (d, 1H); 4.01 (broad q, 1H); 5.00 (quint.,1H); 5.38 (m, 1H); 6.51 (broad d, NH); 7.20 (m, 5H).

Example 2 a) Precursor of formula Bb Wherein R=ethyl, A=methoxyacetyl(diethyl-3-methoxyacetoxyglutaric acid)

50.0 g of diethyl-3-hydroxyglutaric acid (Fluka, Buchs, Switzerland) aredissolved at 0° C. in 80 ml of dichloromethane; 20.6 ml of pyridine and22.9 ml of methoxyacetyl chloride are added and the mixture is stirredat room temperature for about 12 h until all the starting material hasreacted. The mixture is washed in succession with water, 1N hydrochloricacid, saturated sodium hydrogen carbonate solution and saturated sodiumchloride solution. The organic phase is separated and dried overmagnesium sulfate. After evaporation of the organic solvent, adark-yellow syrup is obtained which is filtered over a small amount ofsilica gel using hexane/ethyl acetate (2:1). After evaporation of thesolvent, 65.0 g of NMR-spectroscopically pure methoxyacetate Bb areobtained: ¹H-NMR (CDCl₃): 1.20 (t, 3H); 2.65 (d, 4H); 3.35 (s, 3H); 3.90(s, 2H); 4.04 (q, 4H); 5.55 (quin., 1H).

b) Compound of formula Cb wherein R=ethyl, A=methoxyacetyl(monoethyl-3(R)methoxyacetoxyglutaric acid)

40.0 g of diethyl-3-methoxyacetoxyglutaric acid Bb are suspended at roomtemperature in 150 ml of distilled water, and 43 ml of 0.1M phosphatebuffer (pH 7) are added. After the addition of 0.4 g of α-chymotrypsin(Sigma; Sigma Chemie, Buchs, Switzerland), the mixture is stirredvigorously and maintained at pH 7.8 using a pH meter and pH stat(Metrohm) and 0.5N sodium hydroxide solution. After 18 h, a further 0.1g of chymotrypsin is added and stirring is continued until thetheoretical amount of hydroxide solution has been consumed. The mixtureis then extracted with ethyl acetate (4×). The aqueous phase is adjustedto pH 1 with concentrated hydrochloric acid (conc. HCl) and thenextracted with ethyl acetate. Any cloudiness of the organic phase can beremoved by filtration over Celite. After evaporation of the organicphase, 24.8 g of semi-ester Cb remain: ¹H-NMR (CDCl₃): 1.24 (t, 3H);2.74 (d, 2H); 2.75 (d, 2H); 3.42 (s, 3H); 3.99 (s, 2H); 4.14 (q, 2H);5.59 (quin., 1H).

Alternatively, immobilised chymotrypsin can also advantageously be used.It can be supported on silica gel (Sigma S0507, 230-400 mesh, averagepore diameter 0.6 nm; Sigma Chemie, Buchs, Switzerland) by customarymethods without loss of activity, easily removed and then usedrepeatedly.

c) Determination of the Enantiomeric Excess (ee) of the Monoacid Cb byMeans of Benzamide Db (R=Ethyl, A=Methoxyacetyl)

200 mg of the monoacid Cb are reacted by customary methods of peptidecoupling with 392 mg of(benzotriazol-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate, 290 μl of Hünig's base and 88 μl of benzylamine(Fluka, Buchs, Switzerland) in 2.0 ml of DMF at room temperature. Aftercustomary extraction, 178 mg of amide Db are obtained. HPLC analysis(Chiracel OD 25 cm×0.46 cm (Daicel Chemical Industries, Ltd., JP),n-hexane:ethanol=9:1, flow rate 1 ml/min, UV detection at 210 nm) yieldsa ratio of R to S of 98.6:1.4. ¹H-NMR (CDCl₃): 1.22 (t, I=7.0, 3H); 2.62(d, I=6.5, 2H); 2.75 (dd, I=15.8, 5.3, 2H); 3.35 (s, 3H); 3.91 (s, 2H);4.10 (q, I=7.0, 2H); 4.38 (d, I=5.9, 2H); 5.56-5.65 (m, 1H); 6.31 (t,br, NH); 7.21-7.33 (m, 5H).

d) Purification of the compound Cb wherein R=ethyl, A=methoxyacetyl(monoethyl-3(R)methoxyacetoxyglutaric acid)

500 g of monoacid Cb are dissolved in 2 litres of tert-butyl methylether and heated to boiling. 400 ml (1 eq.) of dicyclohexylaminedissolved in 2 litres of tert-butyl methyl ether are added dropwise inthe course of 10 min, followed by 4 litres of n-hexane. Ifcrystallisation does not start spontaneously, seeding is carried out,followed by cooling to 5-10° C. The resulting crystals are filtered offwith suction and dried in vacuo at 70° C. Yield: 694 g, 80% whitecrystals, m.p.=111° C. 3 g of the resulting salt are dissolved in 20 mlof water, NaCl is added to the solution and 1 eq. of 3N hydrochloricacid is added. The precipitated dicyclohexylamine hydrochloride isfiltered off with suction and the clear filtrate is extracted repeatedlywith tert-butyl methyl ether. After drying and removal of the solvent,1.6 g, 92%, of monoacid Cb are obtained; ee≧99.5%, determined by way ofthe benzamide analogously to c).

Example 3 a) Precursor of formula Bc wherein R=ethyl, A=methoxymethyl(diethyl-3-methoxymethoxyglutaric acid)

97.2 g of diethyl-3-hydroxyglutaric acid A (Fluka) are dissolved at 0°C. together with 210 ml of formaldehyde dimethylacetal in 350 ml ofdichloromethane, and 61.3 g of phosphorus pentoxide are added inportions. The mixture is stirred vigorously overnight, the temperatureof the mixture rising to room temperature. When conversion is complete(TLC monitoring), the mixture is decanted off, diluted with methylenechloride and washed in succession with 2×saturated sodium hydrogencarbonate solution and saturated sodium chloride solution. The organicphase is separated and dried over magnesium sulfate. After evaporationof the solvent, a colourless fluid is obtained which is distilled at98-101° C./0.17 torr. 104.8 g (89%) of a colourless fluid, the titlecompound, are obtained: ¹H-NMR (CDCl₃): 1.15 (t, 3H); 2.53 (m, 4H); 3.24(s, 3H); 4.05 (q, 4H); 4.30 (quin., 1H); 4.58 (s, 2H).

b) Compound of formula Cc wherein R=ethyl, A=methoxymethyl(monoethyl-3(R)methoxymethoxyglutaric acid)

980 mg of diethyl-3-methoxymethoxyglutaric acid Bc are suspended at roomtemperature in 16 ml of distilled water, and 16 ml of 0.1M phosphatebuffer (pH 7) are added. After the addition of 0.5 g of chymotrypsin,the mixture is stirred vigorously and maintained at pH 7.8 using a pHmeter and pH stat (Metrohm) and 0.5N sodium hydrogen carbonate solution.When the theoretical amount of carbonate solution has been consumed, themixture is extracted with ethyl acetate. The aqueous phase is adjustedto pH 3-3.5 with 0.5N hydrochloric acid and then extracted with ethylacetate. Any cloudiness of the organic phase can be removed byfiltration over Celite. After washing of the organic phase withsaturated sodium chloride solution and evaporation of the organic phase,0.67 g (77%) of spectroscopically clean monoacid, the title compound,remain: ¹H-NMR (CDCl₃): 1.24 (t, 3H); 2.69 (m, 4H); 3.34 (s, 3H); 4.13(q, 2H); 4.38 (quin., 1H); 4.68 (s, 2H).

c) Determination of the Enantiomeric Excess (ee) of the Monoacid Cc byMeans of the Amide with Benzylamine

400 mg of the monoacid are reacted by customary methods for peptidecoupling with 760 mg of(benzotriazolyl-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate, 215 μl of Hünig's base and 0.70 ml of benzylamine(Fluka) in 2.0 ml of DMF at from 0° C. to room temperature. Aftercustomary extraction, 567 mg of amide are obtained. HPLC analysis(Chiralcel OD, 25×0.46 cm, n-hexane:ethanol=98:2, 1 ml/min) confirms aratio of R to S of more than 98:2. ¹H-NMR (CDCl₃): 1.19 (t, 3H), 2.48(dd, 2H); 2.56 (dd, 1H); 3.24 (s, 2H); 4.06 (broad q, 1H); 4.34 (m, 3H);4.59 (m, 2H); 7.00 (broad s, NH); 7.20 (m, 5H).

Example 4 a) Precursor of formula Bd wherein R=ethyl,A=2-methoxyethoxymethyl (diethyl-3-(2-methoxyethyl)-oxymethoxyglutaricacid)

At 0° C., 11.23 g of diethyl-3-hydroxyglutaric acid A (Fluka) areintroduced together with 11.8 ml of diisopropylethylamine into 40 ml ofdichloromethane, and 8.6 g of 2-methoxyethoxymethyl chloride (Fluka) areadded. The mixture is stirred vigorously overnight, the temperature ofthe mixture rising to room temperature. The mixture is diluted withmethylene chloride and washed in succession with 2×1N hydrochloric acid,2×saturated sodium hydrogen carbonate solution and saturated sodiumchloride solution. The organic phase is separated and dried overmagnesium sulfate. After evaporation of the solvent, a colourless liquidis obtained, 15.9 g (99%), the title compound. ¹H-NMR (CDCl₃): 1.20 (t,3H); 2.59 (m, 4H); 3.32 (s, 3H); 3.49 (m, 2H); 3.63 (m, 2H); 4.09 (q,4H); 4.36 (quin., 1H); 4.73 (s, 2H).

b) Compound of formula Cd wherein R=ethyl, A=2-methoxyethyl(monoethyl-3(R)-(2-methoxyethyl)-oxymethoxyglutaric acid)

2 g of diethyl-3-(2-methoxyethyl)-oxymethoxyglutaric acid Bd aresuspended at room temperature in 30 ml of distilled water, and 3.3 ml of0.1M phosphate buffer (pH 7) are added. After the addition of 0.1 g ofchymotrypsin, the mixture is stirred vigorously and maintained at pH 7.8using a pH meter and pH stat (Metrohm) and 0.5N sodium hydroxidesolution. When the theoretical amount of hydroxide solution has beenconsumed, the mixture is extracted with ethyl acetate. The aqueous phaseis adjusted to pH 3-3.5 with 0.5N hydrochloric acid and then extractedwith ethyl acetate. Any cloudiness of the organic phase can be removedby filtration over Celite. After washing of the organic phase withsaturated sodium chloride solution and evaporation of the organic phase,1.44 g (79%) of spectroscopically clean monoacid, the title compound,remain: ¹H-NMR (CDCl₃): 1.25 (t, 3H); 2.02 (s, 3H); 2.67 (m, 4H); 3.38(s, 3H); 3.55 (m, 2H); 3.69 (m, 2H); 4.12 (q, 4H); 4.41 (quin., 1H);4.79 (q, 2H).

c) Determination of the enantiomeric excess (ee) of the monoacid Cc bymeans of the amide Dc ((R=ethyl, Ac=2-methoxyethoxymethyl)

380 mg of the monoacid Cd are reacted in accordance with customarymethods for peptide coupling with 682 mg of(benzotriazolyl-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate, 493 μl of Hünig's base and 185 μl ofR-phenylethylamine (Fluka) in 3.0 ml of DMF at from 0° C. to roomtemperature. After customary extraction, 403 mg of amide are obtained.NMR-spectroscopy indicates a diastereoisomeric ratio of greater than95:5 on the basis of the shift difference between the two methoxy groupsin the diastereoisomers. HPLC analysis (Chiralcel OD, 25×0.46 cm,n-hexane:ethanol=95:5, 1 ml/min) confirms the ratio of R to S as 98:2.¹H-NMR (CDCl₃): 1.22 (t, 3H), 1.45 (d, 3H); 2.48 (m, 2H); 2.62 (m, 2H);3.30 (s, ca. 5%); 3.38 (s, 95%); 3.50 (m, 4H); 4.12 (1, 1H); 4.34(quint., 1H); 4.79 (q, 2H); 5.11 (quint., 1H); 6.54 (broad d, NH), 7.34(m, 5H).

Example 5 Glutaric Acid Semihalides of Formula I a) Monoethyl ester of(3R)-acetoxy-glutaric acid chloride 1a (R=ethyl, X═Cl, R′=acetyl)

30.0 g of (3R)-acetoxyglutaric acid monoethyl ester (Ca) are dissolvedin 60 ml of dry dichloromethane to which 20 drops of dry DMF have beenadded, and at 0-5° C. the solution is slowly treated with 21.9 g ofoxalyl chloride. The mixture is then stirred for about 30 min. at 0° C.and then for a further 1.5 h at room temperature until the evolution ofgas can no longer be observed. After evaporation of the solvent, 32.6 gof NMR-spectroscopically pure acid chloride 1a remain. (Colourlessproduct can be obtained after molecular distillation). ¹H-NMR (CDCl₃):1.25 (t, 3H); 2.04 (s, 3H); 2.66 (dd, 1H); 2.70 (dd, 1H); 3.30 (dd, 1H);3.34 (dd, 1H); 4.16 (q, 2H); 5.47 (m, 1H).

b) Monoethyl ester of (3R)-acetoxyglutaric acid bromide 1b (R=ethyl,X═Br, R′=acetyl)

5.0 g of (3R)-acetoxyglutaric acid monoethyl ester (Ca) are dissolved in18 ml of dry dichloromethane to which a drop of dry DMF has been added,and at 0-5° C. the solution is slowly treated with 6.7 g of oxalylbromide. The mixture is then stirred for about 30 min. at 0° C. and thenfor a further 2 h at room temperature until the evolution of gas can nolonger be observed. After evaporation of the solvent, 6.6 g (98%) ofspectroscopically pure acid bromide 1b remain: ¹H-NMR (CDCl₃): 1.21 (t,3H); 2.00 (s, 3H); 2.62 (dd, 1H); 3.39 (dd, 1H); 3.42 (dd, 1H); 4.11 (q,2H); 5.41 (m, 1H).

c) Monoethyl ester of (3R)-methoxyacetoxyglutaric acid chloride 1c(R=ethyl, X═Cl, R′=methoxyacetyl)

21.0 g of monoethyl-3(R)-methoxyacetoxyglutaric acid Cb are dissolved in100 ml of dry dichloromethane to which 40 μl of dry DMF has been added,and at 0-5° C. the solution is slowly treated with 13.9 g of oxalylchloride. The mixture is then stirred for about 4 h, the temperature ofthe mixture rising to room temperature. The mixture is then diluted withethyl acetate and extracted 3× with ice-water, and the organic phase isdried over sodium sulfate. After evaporation of the solvent, 20.9 g ofNMR-spectroscopically pure acid chloride 1c remain: ¹H-NMR (CDCl₃): 1.20(t, 3H); 2.04 (s, 3H); 2.67 (m, 2H); 3.32 (m, 2H); 3.36 (s, 3H); 3.95(s, 2H); 4.09 (q, 2H); 5.52 (m, 1H).

d) Monoethyl ester of (3R)-methoxymethoxyglutaric acid chloride Id(R=ethyl, X═Cl, R′=methoxymethyl)

0.40 g of the monoacid Cc is dissolved in 2 ml of dry dichloromethane towhich 3 drops of dry DMF are added, and at 0-5° C. the solution isslowly treated with 0.18 ml of oxalyl chloride until the evolution ofgas can no longer be observed. After evaporation of the solvent, 0.43 gof acid chloride Id remains: ¹H-NMR (CDCl₃): 1.25 (t, 3H); 2.67 (m, 4H);3.69 (s, 3H); 4.13 (q, 2H); 5.53 (q, 1H); 5.54 (s, 2H).

e) Monoethyl ester of (3R)-(2-methoxyethyl)-oxymethoxyglutaric acidchloride Ie (R=ethyl, X═Cl, R′=2-methoxyethyloxymethyl)

0.53 g of the monoacid Cd is dissolved in 2 ml of dry dichloromethane towhich 2 drops of dry DMF have been added, and at 0-5° C. the solution isslowly treated with 0.21 ml of oxalyl chloride until the evolution ofgas can no longer be observed. After evaporation of the solvent, 0.54 gof acid chloride 1e remains: ¹H-NMR (CDCl₃): 1.21 (t, 3H); 2.55 (m, 1H);2.65 (m, 1H); 3.24 (m, 2H); 3.34 (s, 3H); 3.50 (m, 2H); 3.65 (m, 2H);4.10 (q, 2H); 4.38 (quint., 1H); 4.74 (m, 2H).

Example 6 Preparation of the Compounds 5 and the AssociatedIntermediates 2, 3 and 4 and of Compounds 6; and Also of Compounds 7, 8,9 and 10

(i) (b) 3(R)-Acetoxy-7-chloro-5-oxo-heptanoic acid ethyl ester 2a(R=ethyl, R′=acetyl, X═Cl, Y═H): 10.0 g of acid chloride 1a aredissolved at room temperature in 25 ml of dry ethylene chloride andadded dropwise in the course of 15 min to 16.5 g of aluminiumtrichloride in 50 ml of ethylene chloride, a slight rise in temperaturebeing observed. Dry ethylene gas is passed through the resultingsuspension, the temperature rising to about 40° C. and the suspensionbeing largely dissolved. When the absorption of gas has ceased, themixture is poured into ice-cold saturated sodium chloride solution, andthe organic phase is separated and washed a further 2× with saturatedsodium chloride solution. The resulting oil is decolorised in ether overactivated carbon. 11.1 g of chloride 2a are obtained: ¹H-NMR (CDCl₃):1.17 (t, 3H); 1.93 (s, 3H); 2.59 (m, 2H); 2.79 (m, 2H); 2.85 (dt, 2H);3.65 (t, 2H); 4.04 (broad q, 2H); 5.43 (m, 1H).

(ii) (Conversion according to (b))3(R)-7-Chloro-3-hydroxy-5-oxo-heptanoic acid ethyl ester 2b (R=ethyl,R′═H, X═Cl, Y═H): 0.40 g of the acetylated chlorine compound 2a isdissolved in 2 ml of ethanol and 10 ml of potassium dihydrogen phosphatebuffer (0.05M, pH 7), and 0.01 g of esterase (PLE) (Boehringer Mannheim)is added. The pH is maintained at a constant value using pH stat and0.5M sodium hydroxide solution and the reaction is extracted with ethylacetate when the theoretical amount of base has been consumed. Afterremoval of the solvent, the residue is purified by chromatography onsilica gel. 0.30 g of deacetylated chlorine compound 2b is obtained:¹H-NMR (CDCl₃): 1.22 (t, 3H); 2.49 (m, 2H); 2.65 (m, 2H); 2.91 (m, 2H);3.70 (t, 2H); 4.13 (q, 2H); 4.46 (m, 1H).

(iii) (b) 3(R)-Acetoxy-7,7-dichloro-5-oxo-heptanoic acid ethyl ester 2c(R=ethyl, R′=acetyl, X═Cl, Y═Cl): 10.0 g of acid chloride 1a aredissolved in 12 ml of dry ethylene chloride and at 0° C. added dropwisein the course of 15 min to 110 ml of ethylene chloride. 18.6 g ofaluminium chloride are added to the resulting solution, a slightincrease in temperature being recorded. Vinyl chloride is passed throughthe initially clear solution, with vigorous stirring. After about 30min, a suspension is obtained. When the absorption of gas has ceased,about 90 min, the mixture is poured into ice-cold saturated sodiumchloride solution and then extracted with methylene chloride. Theorganic phase is separated off and washed in succession twice withsaturated sodium chloride solution and saturated sodium hydrogencarbonate solution. After drying over sodium sulfate, a deep-brown oilis obtained which is filtered over Celite and activated carbon usingethyl acetate. In order to separate polymeric material, fractionalfiltration is carried out over a short column of silica gel. 11.5 g ofchloride 2c are obtained: ¹H-NMR (CDCl₃): 1.24 (t, 3H); 2.00 (s, 3H);2.65 (d, 2H); 2.86 (d, 2H); 3.38 (d, 2H); 4.11 (q, 2H); 5.48 (m, 1H);6.08 (t, 1H).

(iv) (b) 3(R)-Methoxymethoxy-7-chloro-5-oxo-heptanoic acid ethyl ester2d (R=ethyl, R′=methoxymethyl, X═Cl, Y═H): The compound is preparedunder conditions analogous to those described for Example 6 (i),starting from 1d.

(v) (b) 3(R)-(2-Methoxyethyl)-oxymethoxy-7-chloro-5-oxo-heptanoic acidethyl ester 2e (R=ethyl, R′=2-methoxyethyl-oxymethyl, X═Cl, Y═H): Thecompound is prepared under conditions analogous to those described forExample 6 (i), starting from 1e.

(vi) (c*) 3(R)-Acetoxy-7-chloro-5-oxo-hept-6-enoic acid ethyl ester 6a(R=ethyl, R′=acetyl, Y═Cl): 11.4 g of chloroketone 2c are dissolved at0° C. in 100 ml of dry diethyl ether, and 5.28 ml of triethylamine areadded. When the reaction has ceased (about 4 h), the mixture isextracted in succession with saturated sodium chloride solution, 1Nhydrochloric acid (2×), sodium hydrogen carbonate solution and saturatedsodium chloride solution. The organic phase is dried over magnesiumsulfate and evaporated off. 7.1 g (71%) of α,β-unsaturated ketone 6a areobtained in the form of a dark-red oil. The material is pure enough forfurther reactions. The ketone can be chromatographed on silica gel. 6a:¹H-NMR (CDCl₃): 1.20 (t, 3H); 1.96 (s, 3H); 2.63 (m, 2H); 2.90 (m, 2H);4.08 (q, 2H); 5.46 (m, 1H); 6.49 (d, 1H, 15.0 Hz); 7.32 (d, 1H, 15.0Hz).

(vii) (Conversion according to (c*))3(R)-Acetoxy-7-iodo-5-oxo-hept-6-enoic acid ethyl ester 6b (R=ethyl,R′=acetyl, Y═I): The chlorine compound 6a, 7.1 g, is dissolved at roomtemperature in 50 ml of dry acetone, and 8.1 g of sodium iodide areadded. A clear red solution is formed, to which 0.36 g of aluminiumchloride is added. A precipitate is formed momentarily. The mixture isstirred for about a further 6 h, then diluted with ether and extractedin succession with saturated sodium chloride solution and water. Afterdrying over sodium sulfate and removal of the solvent, 9.4 g of theiodine compound 6b are obtained, which is further used immediately. Itcan, however, also be further purified by chromatography over silicagel. 6b: ¹H-NMR (CDCl₃): 1.22 (t, 3H); 1.96 (s, 3H); 2.64 (m, 2H); 2.90(m, 2H); 4.10 (q, 2H); 5.47 (m, 1H); 7.12 (d, 1H, 15.0 Hz); 7.88 (d, 1H,15.0 Hz).

(viii) (c*) 3(R)-Acetoxy-5-oxohept-6-enoic acid ethyl ester 6c (R=ethyl,R′=acetyl, Y═H): 1.0 g of chloroketone 2a is dissolved at roomtemperature in 10 ml of dry diethyl ether, and 0.55 ml of triethylamineis added. When the reaction is complete, the mixture is poured intoice-cold 1N hydrochloric acid, and the organic phase is separated andextracted in succession with saturated sodium hydrogen carbonatesolution and saturated sodium chloride solution. The organic phase isdried over magnesium sulfate and evaporated. 0.62 g (71%) ofα,β-unsaturated ketone 6c is obtained after chromatographic purificationover silica gel: ¹H-NMR (CDCl₃): 1.17 (t, 3H); 1.92 (s, 3H); 2.60 (m,2H); 2.92 (m, 2H); 4.06 (broad q, 2H); 5.43 (m, 1H); 5.84 (dd, 1H); 6.21(m, 2H).

(ix) (c*) 3(R)-Methoxymethoxy-5-oxohept-6-enoic acid ethyl ester 6d(R=ethyl, R′=methoxymethyl, Y═H): The compound is prepared starting from2d analogously to Example 6 (viii).

(x) (c*) 3(R)-(2-Methoxyethyl)-oxymethoxy-5-oxohept-6-enoic acid ethylester 6e (R=ethyl, R′=2-methoxyethyl-oxymethyl, Y═H): The compound isprepared starting from 2e analogously to Example 6 (viii).

(xi) (c) 3(R)-Acetoxy-7-azido-5-oxo-heptanoic acid ethyl ester 3a(R=ethyl, R′=acetyl): 2.5 g of chloroketone 2a are dissolved in 5 ml ofdimethylformamide, and 0.68 g of sodium azide and 0.03 g of18-crown-6-ether are added. The mixture is stirred at room temperatureuntil the reaction is complete, then diluted with ethyl acetate andextracted in succession with water and saturated sodium chloridesolution. After evaporation of the solvent, 2.1 g of azide 3a areobtained: ¹H-NMR (CDCl₃): 1.23 (t, 3H); 1.98 (s, 3H); 2.63 (dd, 2H);2.68 (ddd, 2H); 2.83 (dd, 2H); 3.52 (t, 2H); 4.10 (q, 2H); 5.49 (m, 1H).[α_(D)]=−23.4° (c=1, CHCl₃).

(xii) (Conversion according to (c))3(R)-7-Azido-3-hydroxy-5-oxo-heptanoic acid ethyl ester 3b (R=ethyl,R′═H): 0.47 g of azido compound 3a is dissolved in 10 ml of phosphatebuffer (0.05M, pH 7) which contains 2.0 ml of ethanol, and 0.01 g ofChirazyme E1 (PLE, Roche) is added. Using a pH stat and a titrator (0.5MNaOH), the pH is maintained at 7 and the reaction is extracted withethyl acetate when the theoretical amount of sodium hydroxide solutionhas been consumed. The organic phase is then extracted by shaking withsaturated sodium chloride solution and dried over magnesium sulfate.After removal of the solvent and subsequent column chromatography oversilica gel, 0.34 g of deacylated product 3b is obtained: ¹H-NMR (CFCl₃):1.32 (t, 3H); 2.57 (m, 2H); 2.79 (m, 4H); 2.83 (dd, 2H); 3.61 (t, 2H);4.22 (q, 2H); 4.54 (m, 1H).

(xiii) (c) 3(R)-Methoxymethoxy-7-azido-5-oxo-heptanoic acid ethyl ester3d (R=ethyl, R′=methoxymethyl): The compound is prepared starting from2d analogously to Example 6 (xi).

(xiv) (c) 3(R)-(2-Methoxyethyl)-oxymethoxy-7-azido-5-oxo-heptanoic acidethyl ester 3e (R=ethyl, R′=2-methoxyethyl-oxymethyl): The compound isprepared starting from 2e analogously to Example 6 (xi).

(xv) (d) (3R,5R)-7-Azido-3,5-dihydroxy-heptanoic acid ethyl ester 4a(R=ethyl, R′ and R″ each=H): 0.28 g of the ketoazide 3b is dissolved in2 ml of dry THF. A mixture of 2.5 ml of dry methanol and 9.5 ml of dryTHF is introduced into a reaction vessel under an argon atmosphere atroom temperature, and 1.4 ml of triethylborane are added. The mixture isstirred for 1 h at room temperature and then cooled to −65° C. Thestarting material is then added dropwise to the resulting solutionwithin a period of 30 min. At −65° C., a total of 0.054 g of sodiumborohydride is then added in portions and stirring is continued for afurther 1 h at −65° C. The reaction mixture is brought to roomtemperature, diluted with ethyl acetate and extracted with 5% ammoniumchloride solution. The organic phase is separated and dried overmagnesium sulfate. After removal of the solvent, the residue isevaporated a further 5× with 40 ml of methanol and purified bychromatography over silica gel. 0.20 g of oily diol 4a is obtained:¹H-NMR (D₂O): 1.25 (t, 3H); 1.56 (m, 2H); 1.68 (m, 2H); 2.46 (d, 2H);3.34 (m, 2H); 3.97 (m, 1H); 4.14 (q, 2H); 4.25 (m, 1H).

(xvi) (Conversion according to (d))(3R,5R)-7-Azido-3,5-(2′,2′-isopropylidene-dioxy)heptanoic acid ethylester 4b (R=ethyl, R′, R″=together isopropylidene): 0.50 g of thecompound 4a is dissolved in 1 ml of absolute THF, and at roomtemperature 0.25 g of dimethoxypropane and 0.01 g of toluenesulfonicacid are added. After 2.5 h, the reaction mixture is diluted with ethylacetate and extracted in succession with saturated sodium chloridesolution, saturated sodium hydrogen carbonate solution and saturatedsodium chloride solution. After removal of the solvent, 0.50 g ofproduct 4b is obtained: ¹H-NMR (CDCl₃): 1.19 (t, 1H); 1.25 (t, 3H); 1.36(s, 3H); 1.45 (s, 3H); 1.58 (dt, 1H); 1.70 (m, 2H); 2.32 (m, 2H); 2.51(m, 2H); 3.38 (m, 2H); 4.00 (m, 1H); 4.14 (dq, 2H); 4.31 (m, 1H).

(xvii) (Conversion according to (e))(3R,5R)-7-Amino-3,5-(2′,2′-isopropylidenedioxy)heptanoic acid ethylester 5a (R=ethyl, R′, R″=together isopropylidene): 10 g of the compound4b are dissolved in 80 ml of ethanol; 500 mg of 5% palladium on carbonare added and the mixture is hydrogenated in an autoclave at 10 barhydrogen pressure and temperatures of from 20 to 30° C. After about 1 h,the catalyst is filtered off and the mother liquor is concentrated invacuo. 8.4 g of a brownish-green oil, the title compound, are obtained:1H-NMR (CDCl₃): 1.26 (t, 3H); 1.35 (s, 3H); 1.44 (s, 3H); 1.55 (m, 2H);1.69 (m, 2H); 2.36 (dd, 1H); 2.51 (dd, 1H); 2.90 (t, 2H); 3.86 (br s,NH); 4.00 (dddd, 1H); 4.13 (q, 2H); 4.29 (dddd, 1H).

(xviii) (Conversion according to (c*)) 3(R)-Hydroxy-5-oxo-hept-6-enoicacid ethyl ester 6f (R=ethyl, R′═H, Y═H): 11.6 g of crude acetylatedolefin 6c are dissolved in 55 ml of ethanol and 200 ml of potassiumdihydrogen phosphate buffer (0.05M, pH 7), and 0.05 g of esterase (PLE;Boehringer Mannheim) is added. The pH is maintained at a constant valueusing a pH stat and 0.5M sodium hydroxide solution and the reaction ispurified by chromatography with silica gel after the theoretical amountof base has been consumed. 3.1 g of deacetylated olefin 6f are obtained:¹H-NMR (CDCl₃): 1.22 (t, 3H); 2.50 (d, 2H); 2.79 (m, 2H); 2.81 (m, 2H);4.13 (q, 2H); 4.47 (m, 1H); 5.85 (dd, 1H); 6.25 (m, 2H).

(xix) (c′) (3R,5R)-Dihydroxy-hept-6-enoic acid ethyl ester 7a (R=ethyl,R′═H, R″═H, Y═H)

2.60 g of the ketoolefin 6d are dissolved in 20 ml of dry THF. A mixtureof 25 ml of dry methanol and 80 ml of dry THF is introduced into areaction vessel under an argon atmosphere at room temperature, and 14.00ml of triethylborane are added. The reaction mixture is stirred at roomtemperature for 1 h and then cooled to −65° C. The starting material isadded dropwise to the resulting solution within a period of 30 min. At−65° C., a total of 0.58 g of sodium borohydride is then added inportions and stirring is continued for a further 1 h at −65° C. Thereaction mixture is brought to room temperature, diluted with ethylacetate and extracted with 5% ammonium chloride solution. The organicphase is separated and dried over magnesium sulfate. After removal ofthe solvent, the residue is evaporated a further 5× with 40 ml ofmethanol and purified by chromatography over silica gel. 1.80 g of oilydiol 7a are obtained: ¹H-NMR (CDCl₃): 1.21 (t, 3H), 1.61 (m, 2H); 2.44(m, 2H); 3.60 (d broad, OH); 3.92 (d broad, OH); 4.10 (q, 2H); 4.23 (m,1H); 4.33 (m, 1H); 5.03 (dt, 1H); 5.19 (dt, 1H); 5.79 (ddd, 2H).

(xx) (c′) (3R,5S)-3,5-(2′,2′-Isopropylidenedioxy)-hept-6-enoic acidethyl ester 7b (R=tert-butyl, R′ and R″=isopropylidene, Y═H): Thecompound is prepared in accordance with one of the processes describedhereinabove and hereinbelow.

(xxi) (d′) (3R,5R)-3,5-(2′,2′-Isopropylidenedioxy)-6-oxo-hexanoic acidtert-butyl ester 8a (R=tert-butyl, R′ and R″=isopropylidene): 500 mg ofcompound 7b (R=tert-butyl, R′ and R″=isopropylidene, Y═H) are dissolvedin 30 ml of methylene chloride and cooled to −78° C. Ozone is passedthrough the solution until the solution becomes pale blue. Flushing withoxygen is carried out for 5 min before a solution of 500 mg oftriphenylphosphine in 5 ml of methylene chloride is added. The mixtureis stirred at room temperature for 1 h and then concentrated byevaporation. The product is purified by means of flash chromatography,yielding 500 mg (99%) of the aldehyde 8a in the form of colourlesscrystals: ¹H-NMR (CDCl₃): 1.24-1.41 (m, 1H); 1.41 (s, 2H); 1.45 (s, 3H);1.76-1.82 (m, 1H); 2.31 (dd, J=15.1, 6.3, 1H); 2.42 (dd, J=15.1, 7.0,1H); 4.25-4.34 (m, 2H); 9.45 (s, 1H).

(xxii) (e′) (3R,5S)-7-Iodo-3,5-(2′,2′-isopropylidenedioxy)-hept-6-enoicacid tert-butyl ester 9a (R=tert-butyl, R′ and R″=isopropylidene): In a100 ml two-necked flask, 2.83 g of dry CrCl₂ are suspended under argonin 36 ml of absolute THF and cooled to 0° C. A solution of compound 8a(990 mg) and 2.26 g of iodoform (CHI₃) in 18 ml of THF is added dropwiseto the resulting suspension. The mixture is stirred for 16 h at roomtemperature and then poured into 70 ml of water and extracted withether. The combined organic phases are washed with saturated sodiumchloride solution and dried over sodium sulfate. After purification bycolumn chromatography, 470 mg (32%) of the vinyl iodide 9a are obtainedin the form of a yellow oil. The compound consists of 70% E- and 30%Z-isomer. ¹H-NMR (CDCl₃): 1.21-1.39 (m, 1H); 1.40 (s, ca. 3H); 1.44 (s,6.3H); 1.45 (s, ca. 3H); 1.46 (s, 2.7H); 1.53 (s, 0.3H); 1.56-1.78 (m,1H); 2.29 (dd, J=15.4, 6.3, 0.7H); 2.32 (dd, J=15.0, 6.2, 0.3H); 2.44(dd, J=15.3, 7.1, 1H); 4.21-4.38 (m, ca. 2H); 6.23 (dd, J=7.3, 7.3,0.3H, Z); 6.34 (dd, J=7.9, 0.9, 0.3H, Z); 6.30 (dd, J=14.7, 0.9, 0.7H,E); 6.52 (dd, J=14.7, 5.6, 0.7H, E).

(xxiii) (b) 3(R)-7-Chloro-3-methoxyacetoxy-5-oxo-heptanoic acid ethylester 2f (R=ethyl, R′=methoxyacetyl, X═Cl, Y═H): 108.3 g of acidchloride 1c are dissolved in 60 ml of dry ethylene chloride and at 0° C.added dropwise in the course of 1 h to 156.0 g of aluminium trichloridein 500 ml of dry ethylene chloride, a slight rise in temperature beingobserved. Dry ethylene gas is passed through the clear solution, thetemperature rising to about 4-10° C. When the absorption of gas hasceased, the mixture is poured into ice-cold saturated sodium chloridesolution and extracted with ethyl acetate. The organic phase is washedtwice more with saturated sodium chloride solution and dried overmagnesium sulfate. 112.5 g of 2f are obtained in the form of anorange-yellow oil: ¹H-NMR (CDCl₃): 1.25 (t, 3H); 2.70 (m, 2H); 2.90 (m,2H); 3.41 (s, 3H); 3.72 (t, 2H); 3.97 (s, 2H); 4.13 (q, 2H); 5.62 (m,1H).

(xxiv) (b) 3(R)-7-Chloro-3-hydroxy-5-oxo-heptanoic acid ethyl ester 2b(R=ethyl, R′═H, X═Cl, Y═H) (alternative synthesis): 20 g of crude3(R)-7-chloro-3-methoxyacetoxy-5-oxo-heptanoic acid ethyl ester 2f aredissolved analogously to the acetyl derivative 2a (see Example 6 (ii))in 400 ml of water; 1 ml of technical grade PLE (Roche) is added and thepH is maintained at 7 using a pH stat and 0.5N sodium hydrogen carbonatesolution. When the theoretical amount of base has been consumed, thereaction mixture is washed repeatedly with hexane, and the product isthen extracted from the aqueous phase with ethyl acetate, and the ethylacetate phase is then washed with sodium chloride solution. Afterremoval of the solvent, 9.4 g of the chlorine compound 2b remain behindin the form of a colourless liquid having spectroscopic data identicalto those above.

(xxv) (c″) (3R,5R)-7-Chloro-3,5-dihydroxy-heptanoic acid ethyl ester 10a(R=ethyl, R′═H, R″═H, X═Cl, Y═H): 38 ml (1M solution in THF) oftriethylborane are introduced into 75 ml of dry tetrahydrofuran and 55ml of dry methanol under an argon atmosphere at room temperature. Thereaction mixture is stirred for 1 h at room temperature and then cooledto −65° C. 7.77 g of 2b, dissolved in THF, are then added dropwise tothe resulting solution in the course of 30 min. At −65° C., a total of1.45 g of sodium borohydride are then added in portions and stirring iscontinued for a further 1 h at −65° C. The reaction mixture iscautiously treated with 1N hydrochloric acid at −65° C. and brought toroom temperature, diluted with ethyl acetate and extracted withsaturated sodium chloride solution. The organic phase is separated offand dried over magnesium sulfate. After removal of the solvent, theresidue is taken up in 120 ml of THF and at 0° C. cautiously oxidisedwith 12 ml of 35% hydrogen peroxide solution. The reaction mixture isdiluted with ethyl acetate and extracted with saturated sodium chloridesolution, and the organic phase is dried over magnesium sulfate. Afterfiltration and removal of the solvent, an oil remains behind which isadvantageously stirred with methanol in silica gel. 7.0 g of oily diol10 are obtained after filtration and evaporation of the solvent: ¹H-NMR(CD₃OD): 1.25 (t, 3H); 1.65 (m, 2H); 1.89 (m, 2H); 2.48 (d, 2H); 3.64(m, 2H); 3.95 (m, 1H); 4.14 (q, 2H); 4.20 (m, 1H). This material is useddirectly in the next step.

An alternative method for the diasteroselective reduction of 2b to 10 isthe heterogeneous reduction of 2b with hydrogen in the presence ofmagnesium acetate with platinium on carbon.

(xxvi) (c″) (3R,5R)-7-Chloro-3,5-(2′,2′-isopropylidenedioxy)-heptanoicacid ethyl ester 10b (R=ethyl, R′ and R″ together=isopropylidene=H,X═Cl, Y═H): 6.5 g of diol 10a are dissolved in 12.3 ml ofdimethoxypropane, and 0.3 g of toluenesulfonic acid is added. After 4.5h at about 40° C., the reaction mixture is diluted with ethyl acetateand extracted in succession with saturated sodium chloride solution,saturated sodium hydrogen carbonate solution and saturated sodiumchloride solution. After removal of the solvent, 5.3 g of 10b areobtained: ¹H-NMR (CDCl₃): 1.18 (t, 1H), 1.23 (t, 3H); 1.34 (s, 3H); 1.44(s, 3H); 1.57 (dt, 1H); 1.85 (m, 2H); 2.43 (m, 2H); 3.59 (m, 2H); 4.11(m, 3H); 4.30 (m, 1H).

(xxvii) (d″) (3R,5R)-7-Azido-3,5-(2′,2′-isopropylidene-dioxy)heptanoicacid ethyl ester 4b (R=ethyl, R′, R″=together isopropylidene)(alternative method): 4.5 g of chloride 10b are dissolved in 8 ml ofdimethylformamide, and 1.20 g of sodium azide are added. The mixture isstirred at 55° C. until the reaction is complete, then diluted withethyl acetate and extracted in succession with water and saturatedsodium chloride solution. After evaporation of the solvent, 4.3 g ofazide are obtained. The NMR data correspond to those indicated above for4b.

Example 8 Further Use of Compound 5 from Reaction Scheme 11

For the preparation of atorvastatin, a compound 5 is reacted with acompound of formula 17

analogously to the conditions described in WO 89/07598 for the reactionbetween that compound and a compound of formulaH₂N—CH₂CH₂—CH(OR₁₀)(OR₁₁), wherein R₁₀ and R₁₁ are alkyl having up to 8carbon atoms or together are 1,2-(1-methyl)ethylidene, 1,2-ethylidene or1,3-propylidene. Subsequent removal of protecting groups and, ifnecessary, opening of the lactone ring yields atorvastatin.

Example 9 Preparation of Cerivastatin Using the Aldehyde 8

For the preparation of cerivastatin, a compound 8 is reacted with acompound of formula 18

analogously to the conditions described in WO 00/49014 for the reactionbetween Ar—CH₂P(═O)(Ph)₂ (Ar=unsubstituted or substituted heterocyclylor unsubstituted or substituted aryl, such as phenyl, etc.; Ph phenyl)and the compound 8. Subsequent removal of protecting groups and openingof the lactone ring yields cerivastatin.

Example 10 Suzuki Coupling with Compounds of Formula VIII

A compound 9 can be combined with the complementary aryl radicals by C—Clinking under the conditions of a modified Suzuki coupling and thus, forexample, after additional protecting group removal, itavastatin can beprepared.

1. A process for the preparation of statin derivatives which comprisesthe reaction of the intermediate of formula I

wherein X is halogen, acyloxy, activated hydrocarbyloxy, activatedhydrocarbylthio or —N(CH₃)—OCH₃, R_(a) is a hydroxy-protecting group andR_(b) is a carboxy-protecting group, with chain lengthening, includingthe following reaction steps, as described below, wherein theintermediate of formula (I) reacts with an ethylene of formula II

wherein Y_(a) is halogen or hydrogen; there being obtained a ketocompound of formula III

wherein Y_(a) is halogen or hydrogen, X_(a) is halogen or acyloxy, R_(a)is hydrogen, obtainable after removal of a hydroxy-protecting groupR_(a), or a hydroxy-protecting group and R_(b) is a carboxy-protectinggroup; the compound of formula III is reacted further in accordancemethod (2) wherein in accordance with method (2), a compound of formulaIII wherein Y_(a) is hydrogen or halogen, and X_(a) is halogen preferredor acyloxy, while R_(a) and R_(b) are as defined for compounds offormula III, is reacted in the presence of a base, with elimination ofhydrohalic acid HX, to form an olefin of formula VII

wherein Y_(a)′ is hydrogen or halogen, R_(a) is hydrogen or ahydroxy-protecting group and R_(b) is a carboxy-protecting group; thecorresponding compound wherein Y_(a)′ is iodine being prepared, ifdesired, by additional reaction with an iodide salt; and/or a compoundof formula VII wherein Y_(a)′ is hydrogen or halogen, R_(a) is hydrogenor a hydroxy-protecting group and R_(b) is a carboxy-protecting group isthen, if necessary, freed of a hydroxy-protecting group R_(a), ifpresent, and is subsequently reduced diastereoselectively to form asyn-diol compound of formula VIII

wherein R_(a)′ is hydrogen and R_(c)′ is hydrogen, or, after subsequentintroduction of protecting groups, R_(a)′ and R_(c)′ are eachindependently of the other hydrogen or a protecting group, with theproviso that at least one of the two radicals is a protecting group, orR_(a)′ and R_(c)′ together are a bridging hydroxy-protecting group;R_(b) is a carboxy-protecting group, and Y_(a)′ is hydrogen or halogen;and, in a case where the introduction of a bridging hydroxy-protectinggroup is desirable, if necessary, when R_(a)′ and R_(c)′ are eachhydrogen, the bridging hydroxy-protecting group formed by R_(a)′ andR_(c)′ together being introduced using a suitable reagent; and theresulting compound of formula VIII is then cleaved oxidatively to forman aldehyde of formula IX

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogenor a hydroxy-protecting group or together are a bridginghydroxy-protecting group; and R_(b)′ is a carboxy-protecting group; itbeing possible for the compound of formula X to be used directly assynthon for the preparation of statin derivatives, or it is reactedfurther with iodoform, diiodomethane or methyl iodide to form an iodinecompound of formula X

wherein R_(a)′, R_(b)′ and R_(b)′ are as defined for compounds offormula IX; wherein in the processes mentioned above, at any stage, evenwhere not explicitly mentioned, if necessary one or more or all of theprotecting groups present in the compounds of formulae I*, I to XIII areremoved or one or more or all of the functional groups that are not toparticipate in a reaction, or that would interfere with the reaction,are converted into protected groups by the introduction of suitableprotecting groups, and it being possible for the compounds of formulaeI*, I to XIII, where salt-forming groups are present and the reaction inquestion is not impaired, also to be in salt form.
 2. A processaccording to claim 1, for the preparation of statin precursors offormula VII described below, which comprises as reaction steps thereaction of the intermediate of formula I wherein X is halogen, acyloxy,activated hydrocarbyloxy, activated hydrocarbylthio or —N(CH₃)OCH₃,R_(a) is a hydroxy-protecting group and R_(b) is a carboxy-protectinggroup with an ethylene of formula II

wherein Y_(a) is halogen or hydrogen; there being obtained a ketocompound of formula III

wherein Y_(a) is hydrogen or halogen and X_(a) is halogen or acyloxy,R_(a) is hydrogen, obtainable after removal of a hydroxy-protectinggroup R_(a), or a hydroxy-protecting group and R_(b) is acarboxy-protecting group; and conversion thereof by reaction in thepresence of a base, with elimination of hydrohalic acid HX, into anolefin of formula VII

wherein Y_(a)′ is hydrogen or halogen, R_(a) is hydrogen or ahydroxy-protecting group and R_(b) is a carboxy-protecting group; thecorresponding compound wherein Y_(a)′ is iodine being obtainable byadditional reaction with an iodide salt; and at any stage, even wherenot explicitly mentioned, if necessary one or more or all of theprotecting groups present in the compounds of formulae I, III and/or VIIare removed or one or more or all of the functional groups that are notto participate in a reaction, or that would interfere with the reaction,are converted into protected groups by the introduction of suitableprotecting groups, and it being possible for the compounds of formulaeI, III and/or VII, where salt-forming groups are present and thereaction in question is not impaired, also to be in salt form.
 3. Aprocess according to claim 2 for the preparation of a compound offormula VIII described below, which additionally comprises the reactionof the compound of formula VII mentioned in claim 2, which, ifnecessary, is freed of the hydroxy-protecting group Ra, withdiastereoselective reduction to form a syn-diol compound of formula VIII

wherein R_(a)′ is hydrogen and R_(c)′ is hydrogen, or, after subsequentintroduction of protecting groups, R_(a)′ and R_(c)′ are eachindependently of the other hydrogen or a protecting group, with theproviso that at least one of the two radicals is a protecting group, orR_(a)′ and R_(c)′ together are a bridging hydroxy-protecting group;R_(b) is a carboxy-protecting group, and Y_(a)′ is hydrogen or halogen;and, in a case where the introduction of a bridging hydroxy-protectinggroup is desirable, if necessary, when R_(a)′ and R_(c)′ are eachhydrogen, the bridging hydroxy-protecting group formed by R_(a)′ andR_(c)′ together being introduced using a suitable reagent; it beingpossible for the compound of formula VIII, where salt-forming groups arepresent and the reaction in question is not impaired, also to be in saltform.
 4. A process according to claim 3 for the preparation of acompound of formula IX described below, which additionally comprises thereaction of the compound of formula VIII mentioned in claim 3, andoxidative cleavage thereof to form an aldehyde of formula IX

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogenor a hydroxy-protecting group or together are a bridginghydroxy-protecting group; and R_(b)′ is a carboxy-protecting group; itbeing possible for the compound of formula VIII, where salt-forminggroups are present and the reaction in question is not impaired, also tobe in salt form.
 5. A process according to claim 4 for the preparationof a compound of formula X described below, which additionally comprisesthe reaction of the compound of formula IX mentioned in claim 4 withiodoform, diiodomethane or methyl iodide to form an iodine compound offormula X

wherein R_(a)′, R_(b)′ and R_(c)′ are as defined for compounds offormula IX; it being possible for the compound of formula IX, wheresalt-forming groups are present and the reaction in question is notimpaired, also to be in salt form.
 6. A compound of formula I

wherein X is halogen, acyloxy, activated hydrocarbyloxy, activatedhydrocarbylthio or —N(CH₃)OCH₃, R_(a) is hydrogen or ahydroxy-protecting group and R_(b) is a carboxy-protecting group.
 7. Acompound of formula I according to claim 6 wherein X is halogen, R_(a)is hydrogen, lower alkanoyl, lower alkoxy-lower alkanoyl, loweralkoxymethoxy or lower alkoxyethoxymethoxy and R_(b) is lower alkyl. 8.A compound of formula I according to claim 7, selected from thefollowing compounds: monoethyl-3(R)-acetoxyglutaric acid chloride orbromide, monoethyl-3(R)-methoxyacetoxyglutaric acid chloride or bromide,monoethyl-3(R)-methoxymethoxyglutaric acid chloride or bromide andmonoethyl-3(R)-(2-methoxyethoxyethyl)-oxymethoxyglutaric acid chlorideor bromide.
 9. A compound of formula VII

wherein Y_(a)′ is hydrogen or halogen, R_(a) is hydrogen or ahydroxy-protecting group and R_(b) is a carboxy-protecting group.
 10. Acompound of formula VII according to claim 9, selected from the groupconsisting of 3(R)-acetoxy-5-oxohept-6-enoic acid ethyl ester,3(R)-hydroxy-5-oxo-hept-6-enoic acid ethyl ester,3(R)-acetoxy-5-oxohept-6-enoic acid ethyl ester,3(R)-methoxymethoxy-5-oxohept-6-enoic acid ethyl ester,3(R)-(2-methoxyethyl)-oxymethoxy-5-oxohept-6-enoic acid ethyl ester and3(R)-hydroxy-5-oxo-hept-6-enoic acid ethyl ester.
 11. A compound offormula VIII

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogenor a protecting group, or R_(a)′ and R_(c)′ together are a bridginghydroxy-protecting group; R_(b) is a carboxy-protecting group, andY_(a)′ is hydrogen or halogen.
 12. A compound of formula VIII accordingto claim 11 named (3R,5S)-dihydroxy-hept-6-enoic acid ethyl ester.